Background: In a randomized, controlled, 2 x 2 factorial trial on the effect of long-term changes in diet and exercise, a significant reduction in body weight and fat mass was observed. Alterations in leptin and plasminogen activator inhibitor-1 concentrations were previously reported from this study. Objective: We examined the separate and combined effects of a 1-y exercise and diet intervention on several adipokines; adiponectin, interleukin-6 and -8, tumor necrosis factor-α, monocyte chemoattractant protein-1, hepatocyte growth factor, nerve growth factor, C-reactive protein, and resistin. Design: One hundred eighty-eight men with several risk factors for diabetes and cardiovascular disease were randomly allocated to 4 groups: diet, exercise, combined diet and exercise, and control. Results: Plasma adiponectin concentrations remained unchanged, whereas body mass index and fat mass decreased after dietary changes and an increase in physical activity. In the control group, adiponectin concentrations were reduced. Analyzed according to the factorial design, only diet intervention had a significant (P = 0.03) positive effect on plasma adiponectin relative to control, and this effect was largely explained by changes in fat mass. After adjustment for change in percentage body fat, there were significant positive effects on tumor necrosis factor-α in all 3 intervention groups (P = 0.01 for the diet group, 0.03 for the exercise group, and 0.05 for the combined diet and exercise group). Minor changes were observed for the other adipokines. Neither baseline concentrations of nor changes in adiponectin and plasminogen activator inhibitor-1 were significantly correlated to the other adipokines, whereas concentrations of and changes in the other adipokines were significantly correlated. Conclusion: Diet intervention had a significant positive effect on adiponectin concentrations, which is largely explained by a reduction in fat mass.