Fetuin-A is a liver-derived factor that may play a role in insulin resistance and age-related chronic diseases (eg, type 2 diabetes mellitus and cardiovascular [CV] disease). Regular exercise improves CV risk and insulin sensitivity; however, it is unknown whether chronic exercise training is related to circulating levels of fetuin-A. Therefore, this study examined whether plasma fetuin-A levels were related to age and chronic physical activity in men. We hypothesized that chronic physical activity would be related to lower plasma fetuin-A levels in younger and older men. In healthy high-active (HI) and low-active (LO) young (HI, n = 7; LO, n = 8) and older (HI, n = 12, LO, n = 11) men, we determined cardiorespiratory fitness (maximal oxygen uptake), plasma fetuin-A levels, plasma insulin, insulin resistance (homeostasis model assessment of insulin resistance), and the standard risk factors for CV disease. Groups were matched for body mass index. Fetuin-A was significantly higher (~20%) in both young and older LO men compared with their HI counterparts, and fetuin-A was inversely related to maximal oxygen uptake (r = -0.40, P = .014). Plasma fetuin-A levels showed trends to be significantly correlated with insulin (r = -0.34, P = .052) and homeostasis model assessment of insulin resistance (r = 0.33, P = .058) in the older individuals. In younger participants, fetuin-A was related to blood pressure and cholesterol measures. These results indicate that low levels of fetuin-A are related to cardiorespiratory fitness and a number of conventional CV and metabolic disease risk factors independent of age and body mass index. Therefore, the maintenance of low levels of circulating fetuin-A may be a novel mechanism contributing to enhanced insulin sensitivity with regular physical activity.