The relation between high density lipoprotein cholesterol (HDL-C) and the development of myocardial infarction was examined in 2425 subjects, aged 50 to 79 years, who were enrolled in the Framingham Study from 1969 to 1971. After 12 years of follow-up, men in the bottom three quartiles of HDL-C (less than or equal to 52 mg/dl) experienced a 60% to 70% excess of myocardial infarction as compared to men whose HDL-C levels were higher (p less than 0.05). The effect of HDL-C was especially strong in women. In separate comparisons to the 4th quartile of HDL-C (greater than or equal to 67 mg/dl), the risk of myocardial infarction increased from a fourfold excess in the adjacent 3rd quartile (56 to 66 mg/dl, p less than 0.01) to a nearly sixfold excess in the 1st quartile (less than or equal to 46 mg/dl, p less than 0.001). These results persisted after adjusting for age and other risk factors. In addition, a significant effect of HDL-C remained in subjects who had the lowest concentrations of total cholesterol (less than or equal to 192 mg/dl in men and 211 mg/dl in women) in which 29% had levels of HDL-C (less than or equal to 36 mg/dl in men and 46 mg/dl in women) that were associated with a marked elevation in the incidence of myocardial infarction. We conclude that screening for total cholesterol alone in men and women aged 50 and older may not adequately identify the coronary candidate.(ABSTRACT TRUNCATED AT 250 WORDS)