AIMS: In SURMOUNT-5, tirzepatide led to greater body weight (BW) reduction versus semaglutide in adults with obesity without T2D. Health-related quality of life (HRQoL) with tirzepatide versus semaglutide in SURMOUNT-5 was evaluated. MATERIALS AND METHODS: This analysis included on-treatment data from participants who received ≥1 dose of tirzepatide or semaglutide at their maximum tolerated dose. Changes in prespecified Short Form-36 Health Survey Version 2 (SF-36v2) norm-based scores for the Physical Component Summary (PCS), Mental Component Summary (MCS), and each domain, Patient Health Questionnaire-9, and Patient Global Impression of Status for Physical Activity scores were assessed at Week 72. Post hoc analysis of changes in SF-36v2 scores in participants with limited baseline physical function and by BW reduction thresholds was assessed at Week 72. RESULTS: Baseline scores were similar between treatments and among BW reduction categories. At Week 72, PCS scores improved from baseline with both treatments (p < 0.001). However, MCS scores did not show significant improvements from baseline (p > 0.05 for both treatment arms). All domain scores improved (p ≤ 0.008), with greater improvements in General Health (GH) with tirzepatide versus semaglutide (5.45 vs. 4.20; p = 0.003). Participants with limited physical function improved in PCS, Physical Functioning (PF), and GH with tirzepatide versus semaglutide (p ≤ 0.025). Higher BW reductions were associated with more improvement in PCS, PF, Role-Physical, Bodily Pain (BP), GH, and Vitality scores with tirzepatide and semaglutide (pooled). CONCLUSIONS: HRQoL improved with tirzepatide and semaglutide, with greater improvement in GH with tirzepatide, especially in participants with limited baseline physical function. Participants who lost the most BW showed the greatest improvements in PF, BP, and GH.