In order to evaluate the determinants of the metabolic cost for cycle ergometry, we analyzed the relationship between VO2 and leg mass (LM) and total body mass (TBM) in 71 randomly-selected sedentary subjects (34 men), aged 20 to 80. Participants performed constant work rate (WR) tests at 0, 25, and 50 W (at 60 rpm) for 6 minutes in a randomized sequence: gross VO2, gross efficiency, and work efficiency were related to TBM and LM as assessed by dual energy x-ray absorptiometry. We found that gross VO2 and gross efficiency were more strongly related to LM than TBM but work efficiency values were independent of both (P>0.05). Significantly higher values of VO2TBM were found in subjects with large LM/TBM ratios and vice-versa; VO2/LM, however, did not change with anthropometric characteristics. Gross VO2 (mL/min) was predicted by a LM-based equation (10.6 [WR, W] + 16.8 [LM, kg] +75) with a mean error below 5%: this equation predicted the cost more accurately than previous TBM-based formulations (P<0.01). We conclude that leg mass actually provides the preferred frame of reference for predicting the oxygen cost for cycle ergometry at 60 rpm in sedentary subjects, independent of age or gender.