Several prospective studies have demonstrated an association between low serum cholesterol level and subsequent mortality from cancer. This finding was explored in the large cohort (361,662) of men aged 35 to 57 years who were screened for possible randomization to the Multiple Risk Factor Intervention Trial. Mortality follow-up revealed a significant excess of cancer in the lowest decile of serum cholesterol level during the early years of follow-up, which attenuated over time. In contrast, the association between high serum cholesterol and coronary heart disease did not diminish during the average of seven years of follow-up. These findings are consistent with the inference that the association between low serum cholesterol level and cancer is at least in part due to an effect of preclinical cancer on serum cholesterol level. A subset of the cohort (12,866 men) participated in the randomized Multiple Risk Factor Intervention Trial protocol, which called for annual measurements of serum cholesterol level. Among the 150 of these men who died of cancer during the trial, cholesterol level fell 22.7 mg/dL (0.59 mmol/L) more than in the survivors over an equivalent period. These data are consistent with the foregoing inference.