Interleukin-6 (IL-6) mediates many aspects of the exercise-induced acute-phase response, including up-regulation of antioxidant defenses. Moreover, IL-6 synthesis is regulated in part by oxidative stress. This investigation tested the hypothesis that an IL-6-mediated acute-phase response after exercise provides negative-feedback protection against exercise-induced oxidative stress. Healthy young (n=16, 26.4±1.8yr) and older men (n=16, 71.1±2.0yr) ran downhill for 45 minutes at 75% VO₂max prior to and following a 12-week period of supplementation with vitamin E (1000 IU/day) or placebo. Circulating IL-6 and soluble IL-6 receptors, peripheral mononuclear cell production of IL-6, and IL-6 transcripts in muscle were measured before and within a 72-hr time-window following each acute exercise bout. At all time-points plasma IL-6, IL-6 bioavailability and CRP were higher in the older men, yet in response to exercise, young and older subjects experienced similar increases in these factors. Although the magnitude of post-exercise changes in acute-phase variables was independent of age, correlations between plasma, mononuclear cell, and muscle IL-6 and oxidative stress were only evident in young men (R²=0.64,0.35,0.33, respectively). These changes in circulating IL-6 were closely associated with a pro-oxidant state (R²=0.47), while muscle IL-6 mRNA correlated with an antioxidant state (R²=0.65). Supplementation with vitamin E did not affect exercise-induced responses or differences between the young and old men in a consistent manner. Therefore, oxidative stress is linked to the acute-phase response following exercise in young men, but not in older men who had elevated acute-phase reactants, suggesting further research is warranted to determine the basis for these differences.