High-sensitivity C-reactive protein (hs-CRP) is associated with an increased risk of cardiovascular disease and the development of type 2 diabetes mellitus. We analyzed the effects of lifestyle modifications including exercise training on hs-CRP in 47 overweight and obese adults. Subjects were divided into a lifestyle modification group (n=23) (exercise and diet instruction) and a control group (n=24) who did not participate in any lifestyle modification. After 3 months, body weight (80.8+/-11.5 to 73.5+/-10.7 kg, P<.01), total cholesterol (217+/-38.4 to 178.0+/-25.6 mg/dL, P<.01), low-density lipoprotein cholesterol (151.3+/-34.9 to 116.7+/-27.8 mg/dL, P<.01), Vo(2)peak (30.3+/-5.1 to 37.1+/-6.9 mL/[kg . min], P<.01), and log hs-CRP (0.75+/-0.4 to 0.56+/-0.3 mg/dL, P=.01) were significantly improved in the lifestyle modification group, but there was no significant improvement in the control group. Changes in log hs-CRP were associated with changes in Vo(2)peak (r=-0.41, P=.004) and changes in weight loss (r=0.42, P=.004). In stepwise multiple regression analysis, weight loss (P=.034) and improved Vo(2)peak (P=.039) were independent predictors of the changes in hs-CRP. When grouped into quartiles according to decreasing weight and increasing Vo(2)peak, levels of changes in log hs-CRP improved across quartiles of weight loss (P<.05) and improved Vo(2)peak (P<.01). Thus, lifestyle changes including regular exercise training in overweight and obese adults decreased hs-CRP, and this was associated with weight loss and improved Vo(2)peak.