In the last few years, it has been demonstrated that tumor necrosis alpha (TNF-alpha) has important effects on whole-body lipid metabolism. TNF-alpha administration has been found to produce an increase in serum cholesterol levels and increased hepatic hydro-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase activity in mice. The purpose of this study was to test whether plasma levels of the soluble forms of the TNF-alpha receptors 1 and 2 (sTNFR1, sTNFR2) are associated with lipid abnormalities. A total of 36 healthy subjects (19 males, mean age 36.2 +/- 1.9, and 17 females, mean age 34.9 +/- 1.4) were studied. Plasma sTNFR1 levels correlated with total (r = 0.43, P = 0.01) and LDL-cholesterol (r = 0.52, P = 0.002) levels, but not with total or HDL2-HDL3 subfractions of HDL-cholesterol, total plasma triglycerides, VLDL-cholesterol or VLDL-triglycerides (all r < 0.11, P = NS). Plasma sTNFR2 levels also correlated with total (r = 0.44, P = 0.009) and LDL-cholesterol (r = 0.57, P < 0.0001) levels, and negatively with HDL2-cholesterol (r = -0.37, P = 0.029). A stepwise multiple linear regression was constructed to predict total cholesterol levels, with BMI, sex, age, sTNFR1 or sTNFR2 as independent variables. Both sTNFR1 and sTNFR2 were significantly associated with total cholesterol (P = 0.031 and 0.009), contributing to 26 and 19%, respectively, of its variance. In another model in which LDL-cholesterol was substituted for total cholesterol, sTNFR1 or sTNFR2 (P = 0.0084 and 0.0005) were significantly associated with LDL-cholesterol, contributing to 39 and 32% of its variance. In summary, plasma levels of sTNFR1 and sTNFR2 circulate in proportion to total and LDL-cholesterol in healthy subjects.