In clinical trials for weight management, changes in physical function are typically assessed with self-report HRQoL questionnaires. In this trial we aimed to objectively measure the effect of weight loss on walking capacity, as measured with the 6-minute walk test, a sub-maximal exercise test used to assess cardiopulmonary and musculoskeletal systems. The SCALE IBT trial (NCT02963935) was a 56-week, randomized, double-blind, US-based multicenter trial of liraglutide 3.0 mg vs placebo, with intensive behavior therapy (IBT) (i.e. reduced calorie intake, increased physical activity [max target: 250 min/week], and 23 counseling visits) in both arms. A key secondary endpoint was the change in 6-minute walking distance (6MWD), a test for walking capacity measured by total distance walked along a 20-m marked walkway over 6 minutes. To our knowledge, this is the first trial with pharmacological weight management to explore changes in the 6MWD in response to treatment. This post-hoc analysis examined the association between baseline body mass index (BMI) and 6MWD, and change in weight and 6MWD. For the trial, individuals aged ≥18 y with a BMI ≥30 kg/m2 and without diabetes were randomized 1:1 to IBT plus liraglutide 3.0 mg or placebo. The change in body weight and 6MWD from baseline to week 56 was calculated using analysis of covariance (ANCOVA), with treatment, gender and BMI as factors and baseline endpoint [body weight or 6MWD] as a covariate. Linear regression was used for the correlation analysis of the association between 6MWD and BMI. There were 282 individuals in the full analysis set (47 y, 17% male, BMI 39 kg/m2), of whom 142 were randomized to liraglutide 3.0 mg and 140 to placebo. At 56 weeks, mean weight loss was 7.5% with liraglutide 3.0 mg and 4.0% with placebo, estimated treatment difference (ETD [95% CI] 3.5% [1.6, 5.3]; p=0.0003). Improvement in 6MWD was 49.5 m vs. 46.4 m, respectively, from a mean baseline of 439 m (ETD [95% CI] 3.1 [-12.7, 18.9]; p=0.70). The post-hoc correlation analysis showed a linear relationship between 6MWD and BMI. Linear regression of baseline 6MWD vs. baseline BMI showed that on average an individual with a BMI that was 1 kg/m2 lower compared to another individual was able to walk 4.9 m longer in 6 minutes (slope [95% CI] -4.9 m/(kg/m2) [-6.2, -3.6]; p<0.0001). This relationship was also demonstrated in a linear regression analysis of change in 6MWD at 56 weeks vs. change in BMI at 56 weeks, where on average an individual improved 6MWD by 5.0 m for each BMI decrease of 1 kg/m2 (slope [95% CI] -5.0 m/(kg/m2) [-7.6, -2.5]; p<0.0001). The intercept (i.e. change in 6MWD with no change in BMI) was 36.3 m, most likely primarily reflecting the effect of increased physical activity as a part of the IBT intervention. This post-hoc analysis showed that greater weight loss was associated with greater improvements in 6MWD in a linear manner, indicating gains in walking capacity. Supported by Novo Nordisk.