Low serum total cholesterol (TC) is associated with a variety of nonatherosclerotic diseases, but the association of TC with infectious disease has been little studied. In this study, we examined the relationship between serum TC and HIV infection in members of a large health maintenance organization in Northern California. The cohort consisted of 2446 unmarried young men 15 to 49 years of age at high risk of HIV infection, defined as self-reported history of sexually transmitted disease or liver disease. Baseline measurements were taken between 1979 and 1985, and subjects were passively followed for HIV infection until the end of 1993 (average length of follow-up, 7.7 years). From a multivariate-adjusted Cox regression, the rate ratio (RR) of HIV infection was 1.66 (95% CI = 1.07, 2.56) for men with serum TC levels <160 mg/dl compared with those with TC levels between 160 and 199 mg/dl. Similar excess risk of AIDS and AIDS-related death was observed. These findings suggest that low serum TC levels should be considered a marker of increased risk of HIV infection in men already at heightened risk of HIV infection.