ABSTRACT:The aims of this study were to compare baseline Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL‐Lite‐CT) scores between adults with obesity participating in either observational or clinical studies and to conduct a psychometric evaluation of the IWQOL‐Lite‐CT in the context of observational research. Analyses of covariance were used to compare baseline IWQOL‐Lite‐CT Total, Physical, Physical Function, and Psychosocial composite scores between participants with a body mass index (BMI) ≥ 30 in a US longitudinal survey (an observational study) and a multinational phase 3a study of subcutaneous semaglutide 2.4 mg for weight management (STEP 1). Data from the longitudinal survey were also used to evaluate the psychometric properties of the IWQOL‐Lite‐CT composite scores. Adjusting for BMI, age, and sex, on average, participants in the longitudinal survey scored lower than STEP 1 participants at baseline by 23.4 points on the IWQOL‐Lite‐CT Total, 20.7 on the Physical composite, 20.3 on the Physical Function composite, and 24.8 on the Psychosocial composite. While the internal consistency, test–retest reliability, and construct validity of the IWQOL‐Lite‐CT composite scores were confirmed in the longitudinal survey, responsiveness analyses were limited by small changes in weight. The weight‐related functioning of US individuals with obesity who participated in a longitudinal survey was more limited than that of participants in the STEP 1 clinical trial. Psychometric results support use of the IWQOL‐Lite‐CT in observational research in addition to the clinical trial setting.