The aim of the present study was to search for genetic determinants of combined hyperlipidemia and hypertriglyceridemia, and to evaluate whether such determinants might be associated with predisposition to atherosclerosis. Four DNA polymorphisms in the apo AI-CIII-AIV gene cluster (G to A mutation at position -75 basepairs in the apo AI promoter, XmnI, PstI and SstI) were studied in relation to combined hyperlipidemia, hypertriglyceridemia, lipoprotein levels, atherosclerosis and age in 221 Danish men. The frequency of the rare allele of the XmnI polymorphism, the X+ allele, was higher in individuals below 55 years of age with combined hyperlipidemia than in individuals with normal lipid levels (0.31 vs. 0.14; P = 0.05). The rare allele of the SstI polymorphism, the S+ allele, was more frequent in hypertriglyceridemic individuals compared with normotriglyceridemic individuals (0.16 vs. 0.09; P < 0.05) and on analysis of variance the combined S-S+ and S+S+ genotypes were also associated with the highest triglyceride levels. Furthermore, the frequency of the S+ allele decreased significantly as a function of age in nonatherosclerotic subjects (from 0.15 to 0.10 to 0.02 in 48-, 63- and 85-year-olds, respectively; 48- versus 85-year-olds, P = 0.03). These results suggest that genetic variation in the apo AI-CIII-AIV gene complex is associated with combined hyperlipidemia and hypertriglyceridemia and may have an impact on longevity and/or predisposition to atherosclerosis.