Context: GH and IGF-I are nitrogen retaining and anabolic, but the impact of long-term exposure to supraphysiological GH and IGF-I, either from endogenous overproduction in acromegaly or exogenous sources, on skeletal muscle (SM) mass is not clear. Objectives: The objectives of the study were to assess SM mass by whole-body magnetic resonance imaging (MRI) in acromegaly and test the hypothesis that dual-energy x-ray absorptiometry (DXA) lean tissue mass-derived estimates of SM accurately estimate true SM mass. Design, Setting, and Patients: The design was a cross-sectional study in 27 acromegaly patients compared with predicted models developed in 315 nonacromegaly subjects and to matched controls. Outcome Measures: Mass of SM from whole-body MRI and lean tissue from DXA were measured. Results: SM mass did not differ from predicted or control values in active acromegaly: 31.75 ± 8.6 kg (acromegaly) vs. 33.06 ± 8.9 kg (predicted); SM was 95.6 ± 12.8% of predicted (range 66.7-122%) (P < 0.088). Lean tissue mass (DXA) was higher in acromegaly than controls: 65.91 ± 15.2 vs. 58.73 ± 13.5 kg (P < 0.0001). The difference between lean tissue mass (DXA) and SM in acromegaly patients was higher than that in controls (P < 0.0001) consistent with an enlarged non-SM lean compartment in acromegaly. SM mass predicted by DXA correlated highly with SM mass by MRI (r = 0.97, P < 0.0001). SM (MRI) to SM (DXA predicted) ratio was 1.018 (range 0.896-1.159), indicating high agreement of these measures of SM. Conclusions: SM mass in active acromegaly patients did not differ from predicted values. SM mass estimated from DXA agreed highly with SM by MRI, supporting the validity of the DXA model in assessing SM in acromegaly and other disorders of GH/IGF-I secretion.