Background Weight gain after starting antihypertensive medications is a frequent concern for patients, but there is limited data on expected weight change after initiation of these medications. A comparative effectiveness trial to evaluate this outcome would not be feasible. Objective To estimate and compare average weight change under initiating and adhering to commonly prescribed, first-line antihypertensive medications as monotherapy by emulating a target trial. Design Retrospective observational cohort study over 24 months of follow-up using electronic health records (EHR). Participants 141,260 patients prescribed one of seven antihypertensives between 2010 and 2019 across 8 US health systems. Main Outcome and Measures We examined mean weight change associated with initiation of and adherence to amlodipine, atenolol, hydrochlorothiazide, losartan, metoprolol, or propranolol, relative to lisinopril, at 6, 12, and 24 months after initiation. To adjust for baseline confounding and informative outcome measurement, we used inverse probability weighting with repeated outcome marginal structural models. Key Results After baseline and time-varying covariate adjustment, initiation of and adherence to lisinopril were associated with mean weight loss at 6 months (− 0.69 kg, 95% CI − 0.92, − 0.47), 12 months (− 0.58 kg, 95% CI − 1.05, − 0.30), and 24 months (− 1.121 kg, 95% CI − 2.013, − 0.46). Compared to lisinopril, the estimated 6-month weight change was higher for patients prescribed hydrochlorothiazide (0.68 kg, 95% CI 0.31, 1.04), losartan (0.54 kg, 95% CI 0.17, 0.93), metoprolol (1.38 kg, 95% CI 0.95, 1.76), and propranolol (1.03 kg, 95% CI 0.346, 1.62). At 12 months, metoprolol (1.74 kg, 95% CI 1.03, 2.41) and propranolol (1.72 kg, 95% CI 0.06, 3.235) continued to show higher weight change compared to lisinopril. Conclusion We observed small differences in weight change across antihypertensive medications, with lisinopril leading to weight loss and metoprolol and propranolol to modest weight gain. Clinicians should consider potential weight gain when selecting antihypertensive medications.