Interleukin (IL)-10 is an anti-inflammatory cytokine that suppresses pro-inflammatory cytokines. We previously demonstrated that supplementation with vitamins E and C ameliorated the increase in IL-10 immediately following anterior cruciate ligament (ACL) surgery in the absence of other cytokine perturbations. Since both oxidative stress and insulin-like growth factor-1 (IGF-1) can modulate IL-10 concentrations, the mechanisms for these changes warranted further investigation. Our objective was to evaluate the mechanism for the IL-10 decrease following ACL surgery. This study consisted of randomized, double-blind, placebo-controlled experimental design. Subjects were randomly assigned to daily supplementation with either: (i) antioxidants (AO; vitamins E [alpha-tocopherol] and C [ascorbic acid]; n = 10); or (ii) matching placebos (PL; n = 10). Supplementation started approximately 2 weeks prior to surgery (baseline) and concluded 3 months after surgery. Subjects provided six fasting blood samples at: (i) baseline; (ii) immediately pre-surgery (Pre); (iii) 90 min; (iv) 72 h; (v) 7 days; and (vi) 3 months post-surgery. alpha-Tocopherol, ascorbic acid, F(2)-isoprostane and IGF-1 concentrations were measured in each blood sample. At 90 min relative to other times, plasma F(2)-isoprostane concentrations were significantly (P < 0.05) elevated in both groups, while at 90 min IGF-1 was significantly (P < 0.05) lower in the AO compared to the PL group. The changes in IGF-1 at 90 min relative to baseline were correlated (P < 0.0001) with the changes in IL-10. The decrease in IL-10 observed in the AO group is likely dependent on the decrease IGF-1 since lipid peroxidation was unchanged between the two groups.