The associations of serum lipid and lipoprotein levels with the risk of cancer mortality were assessed in 2,753 men and 2,476 women aged 40-79 years at baseline (1972-1976) who participated in the Lipid Research Clinics Program Mortality Follow-up Study through 1984. Seventy-nine cancer deaths occurred in men and 65 occurred in women during an average follow-up time of 8.4 years. Total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly inversely associated with overall cancer mortality in men, but no relation was observed in women. Neither high-density lipoprotein (HDL) cholesterol nor triglycerides were significantly related to total cancer mortality in either sex, although in women. HDL cholesterol was positively associated with risk of death from gynecologic cancers. Compared with men with higher cholesterol levels, the relative risk of death from colon cancer, adjusted for age, body mass, cigarette smoking, and alcohol consumption, was 5.20 (95 percent confidence interval (Cl) 1.61-16.8) in men with total cholesterol levels less than or equal to 187 mg/dl and 4.79 (95 percent CI 1.37-16.8) in those with LDL cholesterol levels less than or equal to 119 mg/dl. Death from smoking-related cancers was inversely related to baseline total cholesterol but not to LDL cholesterol. The absence of an association with HDL cholesterol, which has been shown to be lower in persons with clinically manifest malignancy, and evidence from survival curves suggest that the inverse relation in men is not due to preexisting disease.