Background: In SURMOUNT-1, a phase 3, 72-week, randomized, double-blind clinical trial in participants with obesity, tirzepatide, a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, resulted in significantly greater weight reduction than placebo. Changes in participantreported health-related quality of life (HRQoL) were also assessed in the SURMOUNT-1 trial using the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) instrument. Methods: The IWQOL-Lite-CT (20 items) was collected at baseline and endpoint of the primary treatment period (week 72 or early discontinuation). Participants with complete data were included in the analysis; tirzepatide 5 mg, N=545; tirzepatide 10 mg, N=539; tirzepatide 15 mg, N=535; placebo, N=477. The physical function (5 items) and psychosocial (13 items) composite scores were calculated. The sum of all items provided the total score. Scores were transformed to a scale of 0 to 100 (representing poorest to best quality of life). Change in transformed scores from baseline to endpoint (last nonmissing value prior to treatment discontinuation) were analyzed using an analysis of covariance (ANCOVA) model. Results: Mean scores at baseline with tirzepatide 5 mg, 10 mg, and 15 mg doses and placebo were: total, 64.2, 61.9, 63.0, and 63.2; physical function, 64.4, 61.9, 63.3, and 64.0; and psychosocial, 64.3, 62.1, 63.2, and 63.2, respectively. Significant improvements in all scores were observed with tirzepatide 5 mg, 10 mg, and 15 mg doses compared with placebo at endpoint (all p<0.001): mean total score increased by 18.6, 21.2, and 22.6, versus 10.5; mean physical function score increased by 17.8, 20.7, and 21.8, versus 10.1; and mean psychosocial score increased by 19.6, 22.1, and 23.6 versus 11.0, respectively. Conclusions: In SURMOUNT-1, the IWQOL-Lite-CT indicated significantly improved physical and psychosocial function among participants treated with tirzepatide versus placebo.