IMPORTANCE Post-acute sequelae of SARS-CoV-2 infection (PASC) remains a major public health challenge. While previous studies have focused on characterizing PASC and identifying its subphenotypes in children and adolescents following an initial SARS-CoV-2 infection, the risks of PASC with Omicron-variant reinfections remain unclear. Using a real-world data approach, this study investigates the risks of PASC following reinfections during the Omicron phase in the pediatric population. OBJECTIVE To investigate the risks of PASC diagnosis and 24 PASC symptoms and conditions after reinfection of SARS-CoV-2 during Omicron period in the pediatric population. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used data from the RECOVER consortium comprising 40 children’s hospitals and health institutions in U.S. between January 2022 and October 2023. EXPOSURES A second SARS-CoV-2 infection, confirmed by a positive polymerase-chain-reaction (PCR) or antigen tests, or a diagnose of COVID-19, occurring at least 60 days after the initial infection, compared to the initial infection. MAIN OUTCOMES AND MEASURES PASC was identified using two approaches: (1) the ICD-10- CM diagnosis code U09.9 and (2) a symptom-based definition including 24 physician-identified symptoms and conditions. Absolute risks of incident PASC were reported, and relative risks (RRs) were calculated by comparing the second infection episode with the first infection episode groups using a modified Poisson regression model, adjusting for demographic, clinical, and healthcare utilization factors through exact matching and propensity scoring matching. RESULTS A total of 465,717 individuals under 21 years old (mean [SD] age 8.17 [6.58] years; 52% male) were included. Compared to the first infection, a second infection was associated with significantly increased risk of an overall PASC diagnosis (RR, 2.08; 95% confidence interval [CI], 1.68-2.59), and with many specific conditions including: myocarditis (RR, 3.60; 95% CI, 1.46-8.86); changes in taste and smell (RR, 2.83; 95% CI, 1.41-5.67); thrombophlebitis and thromboembolism (RR, 2.28; 95% CI, 1.71-3.04); heart disease (RR, 1.96; 95% CI, 1.69 to 2.28); acute kidney injury (RR, 1.90; 95% CI, 1.38 to 2.61); fluid and electrolyte (RR, 1.89; 95% CI, 1.62 to 2.20); generalized pain (RR, 1.70; 95% CI, 1.48 to 1.95); arrhythmias (RR, 1.59; 95% CI, 1.45-1.74); abnormal liver enzyme (RR, 1.56; 95% CI, 1.24 to 1.96); fatigue and malaise (RR, 1.50; 95% CI, 1.38 to 1.64); musculoskeletal pain (RR, 1.45; 95% CI, 1.37 to 1.54); abdominal pain (RR, 1.42; 95% CI, 1.34 to 1.50); postural orthostatic tachycardia syndromes (POTS)/dysautonomia (RR, 1.35; 95% CI, 1.20 to 1.51); cognitive functions (RR, 1.32; 95% CI, 1.15 to 1.50); and respiratory signs and symptoms (RR, 1.29; 95% CI, 1.25 to 1.33). The risks were consistent across various organ systems, including cardiovascular, respiratory, gastrointestinal, neurological, and musculoskeletal systems. CONCLUSIONS AND RELEVANCE Children and adolescents face significantly higher risk of various PASC outcomes after reinfection with SARS-CoV-2. These findings suggest a cumulative risk of PASC and highlight the urgent need for targeted prevention strategies to reduce reinfections, which includes an increased emphasis on initial or re-vaccination of children. Question Do children and adolescents face an increased risk of post-acute sequelae of SARS-CoV-2 infection (PASC) following reinfection during the Omicron era? Findings During the post-acute phase, children and adolescents with reinfection are at statistically significant increased risk of incident PASC outcomes, including an overall PASC diagnosis and 24 most commonly complaints/symptoms/diagnoses associated with PASC. The risks remained consistent across different demographic and clinical subgroups. Meaning These findings underscore the significant long-term health risks associated with SARS-CoV-2 reinfection in children and adolescents. Public health strategies should prioritize reinfection prevention, including enhanced vaccination efforts, to mitigate the burden of PASC in the pediatric population. ### Competing Interest Statement Dr. Jhaveri is a consultant for AstraZeneca, Seqirus, Gilead, Sanofi; receives an editorial stipend from the Pediatric Infectious Diseases Society; research support from GSK; and royalties from Up To Date/Wolters Kluwer. All other co-authors have no conflicts of interest to report. ### Funding Statement This research was funded by the National Institutes of Health (NIH) Agreement OT2HL161847-01 as part of the Researching COVID to Enhance Recovery (RECOVER) program of research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethnics committee/IRB of University of Pennsylvania waived ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request. The results reported in this study are based on detailed individual-level patient data compiled as part of the RECOVER program. Due to the high risk of reidentification based on the number of unique patterns in the date, patient privacy regulations prohibit us from releasing the data publicly. The data are maintained in a secure enclave, with access managed by the program coordinating center to remain compliant with regulatory and program requirements. Please direct requests to access the data, either for reproduction of the work reported here or for other purposes, to the RECOVER EHR Pediatric Coordinating Center (recover{at}chop.edu).