Several studies have shown that low physical fitness is associated with high levels of C-reactive protein (CRP), a marker of future cardiovascular events. However, whether increasing physical fitness proportionally decreases the circulating CRP level has not been evaluated. We first evaluated the basic relationship between physical fitness, assessed by running velocity, and circulating CRP level along with cardiovascular risk factors in 1065 healthy middle-aged men. Afterward, we examined the association between annual change in fitness and changes in CRP level in 482 subjects who had the same parameters measured 1 year later without any intervention. In the cross-sectional study, physical fitness was significantly correlated with circulating CRP level (r = 0.28, P < .0001). This significance still remained after adjustment for other cardiovascular risks (β = −.12, P = .0004). In the follow-up study, several variables, including CRP, were significantly improved (CRP geometric mean, from 0.35 to 0.26 mg/L; P < .001). Improvements in fitness did not reach statistical difference (P = .067). Annual change in CRP was significantly correlated with creatinine kinase level 1 year later (r = 0.16, P = .004) and with annual changes in some other risks, but not with annual change in fitness. When follow-up subjects were divided into tertiles according to increase in fitness, the greatest reduction in CRP was found in subjects with mildly increased fitness and favorable risk profiles (n = 159; CRP geometric mean, from 0.35 to 0.21 mg/L; P < .0001), but not in those with moderately to highly increased fitness (n = 113; geometric mean, from 0.36 to 0.28 mg/L; P = .03). In conclusion, although physical fitness was significantly associated with circulating CRP level in a cross-sectional study, increasing fitness did not proportionally decrease circulating CRP level. Improving coincidental risks, relieving intensity of exercise-induced muscle damage, or both, in addition to increasing fitness, might be important to effectively reduce CRP level.