ObjectivesThis study aimed to examine fat‐free mass (FFM) loss between successful responders to lifestyle intervention alone compared with lifestyle intervention plus liraglutide 3.0 mg. An additional objective was to examine the effects of varying resistance training frequencies (days per week) on FFM retention.MethodsThis prospective study examined patients with BMI ≥ 35 kg/m2 receiving treatment in a tertiary care obesity clinic. Body composition (dual‐energy x‐ray absorptiometry) was captured at baseline and after 16 weeks of treatment. Exercise‐related data (aerobic minutes per week and resistance training frequency) were captured at week 16. A total of 78 individuals were examined in two groups, the first with lifestyle intervention alone (n = 19) and the second with lifestyle intervention plus liraglutide 3.0 mg (n = 59). Linear mixed‐effects models were used to examine between‐group differences.ResultsCompared with lifestyle intervention alone, participants on liraglutide lost more weight (−12.2 kg vs. −9.7 kg, P = 0.048) and FFM (−2.3 kg vs. −1.5 kg, P = 0.06). After controlling for weight loss, there was no difference in FFM loss between groups (0.14 kg/wk vs. −0.09 kg/wk, P = 0.12). Absolute weight loss (kilograms) was associated with FFM loss (kilograms) (ρ = 0.58, P < 0.0001). Exercise did not increase weight loss, and resistance training frequency (days per week) did not attenuate FFM loss.ConclusionsLiraglutide does not have effects on FFM beyond what can be expected from total weight loss. Resistance training did not attenuate FFM loss in the liraglutide or lifestyle‐alone groups. To ameliorate FFM loss after liraglutide, a new strategy may be needed that may combine exercise with specific nutritional interventions.