This study examines the independent and interactive effects of family history scores (FHxS) for the prevalence of ischemic heart disease with plasma lipids and subsequent morbidity and mortality from ischemic heart disease. FHxS were calculated for 514 sets of middle aged male twins who participated in the entry examination of the NHLBI Veteran twin study in 1969-1973. Comparison of the FHxS with the level of plasma total cholesterol and HDL cholesterol (HDLc) paralleled earlier reported findings in young adults; individuals with high total cholesterol in two exams 8-12 years apart had significantly (P less than .01) higher FHxS. The same relationship was noted when using the mean twin-pair cholesterol level at the initial exam when the twins were in their 40s. Using the pair means over two exams as the cotwins aged into their 50s, the association of FHxS with total cholesterol declined and pairs with HDLc persistently in the highest quintile at both exams had significantly (P less than .01) lower FHxS. The changes in the pattern of association of lipid fractions with FHxS with age parallel the reported age decline of total cholesterol as a risk factor for heart disease. Assessment of ischemic heart disease events up to January 1988 revealed a highly significant association (P less than .0001) of later ischemic heart disease events with FHxS. At each level of lipid categorization pairs who later had events had higher FHxS than those without any subsequent heart disease; these differences were significant in all but the low risk lipid groups (low total cholesterol, high HDLc, and low total cholesterol/HDLc ratio). We conclude that FHxS is related to total cholesterol and HDLc but also is an independent predictor of subsequent ischemic heart disease after 14-18 years of follow-up.