ABSTRACT: This study aimed to evaluate the hypothesis that exercise attenuates the reductions in lean mass, muscle strength, bone mineral density, and V?O2max that accompany modest weight loss induced by calorie restriction (CR).Overweight, sedentary women and men (n = 52, 45-65 yr) were randomized to 6%-8% weight loss by using CR, endurance exercise training (EX), or both (CREX). The CR and the CREX groups underwent counseling to reduce energy intake by 20% and 10%, respectively. The EX and the CREX groups exercised 7.4 ± 0.5 and 4.4 ± 0.5 h·wk, respectively. Before and after 16.8 ± 1.1 wk of weight loss, lean mass and bone mineral density were measured with dual-energy x-ray absorptiometry, strength was measured with dynamometry, and aerobic capacity (V?O2max) was measured with indirect calorimetry during maximal-intensity treadmill exercise.Weight loss was ~7% in all groups. Decreases in whole-body (~2%, P = 0.003) and lower extremity (~4%, P < 0.0001) lean mass occurred in the CR group (both P < 0.05). Despite similar weight loss, these reductions were attenuated in the CREX group (~1%, P = 0.44 and ~2%, P = 0.05, respectively) and absent in the EX group. Absolute aerobic capacity decreased ~6% in the CR group (P = 0.04), was unchanged in the CREX group (P = 0.28), and increased ~15% in the EX group (P < 0.0001). No changes in muscle strength or bone were observed.Modest weight loss (~7%) induced by 20% CR in overweight women and men decreases lean mass and reduces absolute V?O2max. Exercise protects against these effects. Although the CR-induced changes might be considered physiologically appropriate for a reduced body weight, exercise preserves and/or improves these parameters during weight loss, which likely improves physical function. These findings support the notion of using exercise as an important component of weight loss programs.