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), Vo2peak (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 Vo2peak (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 Vo2peak (P = .039) were independent predictors of the changes in hs-CRP. When grouped into quartiles according to decreasing weight and increasing Vo2peak, levels of changes in log hs-CRP improved across quartiles of weight loss (P < .05) and improved Vo2peak (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 Vo2peak.