The relation between serum cholesterol and cancer incidence was investigated in the population of the Hypertension Detection and Follow-up Program. During the 5 years of follow-up, 286 new cancer cases were documented among the 10,940 participants. Overall, age-adjusted cancer incidence rates, computed by baseline serum cholesterol quartiles, showed a small, but statistically significant, inverse relation between serum cholesterol and cancer incidence. No evidence suggested that the observed relationship was primarily due to confounding by other cancer risk factors, association of low serum cholesterol with incipient but undiagnosed cancer, or problems of competing risks. However, the relationship is weak and a causal interpretation of these immediate results cannot be argued persuasively. Examinations of specific cancer sites and factors related to serum cholesterol are suggested as important lines of research toward clarification of the complex relationships observed.