Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial, once-weekly semaglutide 2.4 mg improved symptoms, physical limitations and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary endpoints across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline; and on all key summary and individual KCCQ domains. STEP-HFpEF randomized 529 participants with symptomatic HF, EF ≥45% and BMI of ≥30 kg/m to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary endpoints were change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary endpoints included change in 6-minute-walk-distance (6MWD), a hierarchical composite endpoint (death, HF events and change in KCCQ-CSS and 6MWD) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary and select exploratory endpoints (NTproBNP) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. Baseline median KCCQ-CSS across tertiles was 37, 59 and 77 points, respectively. Semaglutide consistently improved primary endpoints across KCCQ tertiles 1-3 (estimated treatment differences (ETD;95% CI): for KCCQ-CSS, 10.7 (5.4,16.1), 8.1 (2.7,13.4), 4.6 (-0.6,9.9) points; for body weight, -11 (-13.2,-8.8), -9.4 (-11.5,-7.2), -11.8 (-14.0,-9.6)%, respectively; P=0.28 and 0.29, respectively); same was observed for, confirmatory secondary and exploratory endpoints (P>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (ETD: 6.7-9.6 points across domains; ≤0.001 for all). Greater proportion of semaglutide- versus placebo-treated patients experienced at least 5-, 10-, 15- and 20-point improvements in all KCCQ domains (Odds Ratios: 1.6-2.9 across domains; <0.05 for all). In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight and NTproBNP regardless of baseline health status. Benefits of semaglutide extended to all key KCCQ domains.