Semaglutide (sema) treatment results in substantial weight loss in adults with overweight and obesity.In this analysis we investigated the changes in body composition and muscle strength as a result of sema-induced weight loss.In this phase 3b RCT, adults with BMI ≥30 kg/m2 without T2D were randomized 5:1:1 to sema 7.2 mg, sema 2.4 mg, or placebo for 72 weeks with lifestyle intervention. A MRI subpopulation had body composition measured from knees to T9: total adipose tissue (AT: subcutaneous + visceral [VAT]) and lean tissue (LT). Outcomes at week 72 included % body-weight change, absolute (L) and % changes in AT, VAT, LT, and AT:LT ratio. Volumes were converted to mass using densities (AT 0.92 kg/L; LT 1.1 kg/L). Muscle strength was assessed by a 30-s sit-to-stand test. Data are from MRI participants during the in-trial period, pooled across sema doses under the treatment-policy estimand.Among MRI-scanned patients (sema n=49; pbo n=6), mean baseline weight was 110.8 kg. Baseline tissue volumes were—sema vs pbo: AT 42.9 L vs 47.1 L; VAT 5.4 L vs 5.1 L; LT 23.8 L vs 24.5 L. Sema produced greater % weight loss versus pbo (ETD −16.5% [95% CI −26.3, −6.8]; p=0.0009), larger reductions in total AT (ETD −11.1 L [−16.5, −5.7]; p<0.001) and VAT (ETD −1.5 L [−2.9, −0.1]; p=0.042). LT fell in the sema group but not significantly versus pbo (ETD −1.7 L [−4.0, 0.7]; p=0.164). Estimated mass losses were 10.2 kg (AT), 1.4 kg (VAT), and 1.9 kg (LT); 84.5% of weight lost was from AT and 15.5% from lean mass. Percent changes in AT, VAT, and LT were similar, and AT:LT ratio improved more with sema (1.80→1.35) than pbo (1.93→1.85).There were no differences between sema and pbo in the change from baseline in number of repetitions performed in the sit-to-stand test (ETD −0.1 [−3.6, 3.4]; p=0.97).Weight loss associated with sema treatment was accompanied by clinically important reductions in total AT and VAT, with a small fraction of weight lost from LT, alongside preserved sit-to-stand capability.