Background Acromegaly is associated with changes in body composition. Long-term changes following acromegaly treatment and the impact of different treatments have been less investigated. Methods We performed a retrospective study in 201 patients with acromegaly. Body composition was assessed by dual-energy X-ray absorptiometry. To investigate the specific effects of treatment vs aging, changes in body composition were compared in one group of patients evaluated both at the time of active and controlled disease (active-to-controlled (A>C); n = 31) and in another group of patients evaluated two times while the disease was controlled (controlled-to-controlled (C>C); n = 32). Results In the whole cohort, insulin-like growth factor I (IGF-I) was correlated with fat (r = −0.369; P < 0.001) and lean mass (r = 0.383; P < 0.001). Patients from A>C and C>C groups were comparable for age, sex, BMI and follow-up duration (P = n.s.). Reduction in IGF-I levels was associated with an increase in fat mass and a decrease in lean mass in the A>C group, which was four and eight times more pronounced compared to the C>C group (fat mass: +39 ± 34% vs +10 ± 15%, P < 0.001; lean mass: −8 ± 8% vs −0.2 ± 6%, P < 0.001, respectively). Changes in fat mass were negatively associated with IGF-I (r = −0.450; P = 0.011) and independent of the individual therapy. The daily dose of pegvisomant correlated with fat mass (r = 0.421; P = 0.002) and insulin sensitivity index (r = −0.466; P < 0.001). Conclusions Treatment of acromegaly strongly impacts body composition until biochemical disease remission, characterized by an increase in fat mass and a decrease in lean mass. These changes are closely associated with the normalization of IGF-I. Thereafter, body composition changes are similar to what is observed with aging.