This study investigated the influence of age, body composition, physical fitness, training volume and intensity, and underlying systemic inflammation on exercise-induced inflammation and innate immune function in a heterogeneous group of cyclists. Subjects included 31 male cyclists (mean ± standard deviation, age 38.8 ± 10.6 years, body fat 17.8%± 5.6%, VO(2max) 55.8 ± 8.4 mL kg(-1) min(-1)) who cycled for 1.75 h at 60% watts(max) followed by a 10-km time trial (18.3 ± 0.3 min). Blood samples were collected pre-, post-, and 1-h-postexercise, and analyzed for WBCs, 9 cytokines [interleukin (IL)-6, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-1β, IL-2, IL-8, IL-10, and IL-12p70], and granulocyte and monocyte phagocytosis (GR-PHAG and MO-PHAG) and oxidative burst activity (GR-OBA and MO-OBA). Exercise-induced changes varied widely, with significant increases measured for 8 of 9 cytokines, GR-PHAG (mean change 99%) (95% confidence limits, 69%, 128%) and MO-PHAG (43%) (28%, 58%), and WBC (160%) (133%, 187%), and decreases for GR-OBA (-30%) (-43%,-16%) and MO-OBA (-23%) (-36%,-10%). Correlation and stepwise regression analysis revealed that changes in these variables were not related to age, body fat percentage, VO(2max), training volume, or pre-exercise C-reactive protein. Performance measures, specifically the average heart rate and rating of perceived exertion, were correlated with changes in several variables, including IL-8 (r=0.68 and 0.67, respectively, P<0.001) and IL-6 (r=0.51, P=0.004, and r=0.46, P=0.011, respectively). In summary, variance in exercise-induced inflammation and innate immunity in male cyclists in response to 2 h of endurance exercise is best explained by exercise intensity.