In a previous retrospective study, we reported a significant reduction in serum cholesterol levels following major surgery, and speculated on the possible role of cytokines in this reduction. The purpose of this article is to report a prospective study of the association of cytokines with postoperative changes in serum lipoprotein levels. Serum samples were obtained from 11 male patients before and at intervals for up to 10 days after surgery, and were assayed for total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), cortisol, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma). LDL-C was calculated. The TC showed a 27.9% decrease, from a mean of 4.27 mmol/L to 3.08 mmol/L (p < 0.001) after surgery, reaching a nadir at 24 hours and returning to preoperative values in 7 to 10 days. A similar decrease was noted in the HDL-C and LDL-C levels. IL-6 levels increased from a mean baseline value of 6 pg/ml to a peak of 143 pg/ml at 24 hours (p < 0.0006). There was an inverse relationship between TC and IL-6 levels, with r = -0.51 for the entire curve and r = -0.90 for the cholesterol nadir with the IL-6 peak. The other cytokines did not show significant changes. We conclude that TC and its fractions decrease to a nadir and that IL-6 increases to a peak approximately 24 hours after major surgery. There is a significant inverse correlation between TC and IL-6, suggesting a possible role of IL-6 in postoperative changes in serum lipoproteins.