The prevalence of the metabolic syndrome (MetSyn) approaches 50% in postmenopausal women. This study examines the efficacy of lifestyle modification for the treatment of MetSyn and its associated risk for cardiovascular disease and diabetes in this population. This prospective controlled study examines the effects of a 6-month weight loss and low-intensity exercise program (WL+LEX) on body composition (dual-energy X-ray absorptiometry and abdominal computed tomography scans), fasting glucose and lipid levels, cytokines, and blood pressure in postmenopausal women with and without MetSyn. WL+LEX reduced body weight (MetSyn: -5% vs non-MetSyn: -7%) and fat mass (-11% vs -15%) and increased VO(2max) (+2% vs +3%) in both MetSyn (N = 35) and non-MetSyn (N = 41) groups. Constituents of MetSyn decreased comparably in both groups. Fifteen (45%) MetSyn participants responded (R) by converting to non-MetSyn, 18 remained MetSyn (NR), and 2 had missing data. Reduction in fat mass (-15% vs -8%, p = .02) was greater in R than NR, but there were no between-group differences in changes in VO(2max), cytokines, or other variables. The decrease in the number of MetSyn criteria was greater in R than in NR (-27 vs -13, p < .0001) due to decreases in blood pressure (p < .01), glucose (p = .02), and with a trend for triglyceride (p = .07). Reductions in fat mass best predicted resolution of MetSyn (p = .04). Women who lose more fat are more likely to lower blood pressure, glucose, and triglyceride levels to resolve MetSyn. Thus, a WL+LEX program effectively treats postmenopausal women with MetSyn.