Acetic and propionic acids, produced by colonic fermentation of unabsorbed carbohydrates, may influence systemic lipid metabolism. To determine whether the ratio of the concentrations of acetate to propionate in peripheral serum of fasting humans was related to serum cholesterol, we studied 62 men [age 45 +/- 17 y (mean +/- SD), range 19-74 y; body mass index 25.0 +/- 2.8 kg/m2] and 69 women [43 +/- 18 y, (range, 18-77 y); body mass index 23.0 +/- 3.1 kg/m2] with normal serum lipid concentrations. The concentrations of serum acetate, propionate and butyrate (means +/- SD) were similar in men (98 +/- 33, 3.8 +/- 1.5 and 2.3 +/- 1.5 micromol/L, respectively) and women (92 +/- 38, 3.9 +/- 1.9 and 2.3 +/- 1.6 micromol/L). There were significant positive relationships between the serum acetate:propionate ratio and total cholesterol (r = 0.466, P = 0.0002) and LDL cholesterol (r = 0.384, P = 0.0023) in men, but in women the relationships were not significant (R = 0.174, P = 0.15 and r = 0.135, P = 0.27, respectively). The relationships in men remained significant after adjustment for age and body mass index. These data support the hypothesis that, at least in men, colonic short-chain fatty acids influence systemic lipid metabolism. The relationships among the factors influencing colonic short-chain fatty acid production, the enterohepatic circulation of endogenous estrogens, dietary phytoestrogens and blood lipids in women, however, need further clarification.