An explanation for the consistently documented finding of higher levels of high density lipoprotein-cholesterol in black men relative to white men was sought by comparing the frequency of restriction fragment length polymorphism markers present in blacks and in whites at the gene loci coding for the two major apolipoprotein constituents of high density lipoprotein, apolipoproteins AI and AII. The measurements were made in population-based samples of 45 to 54-year-old black (n = 190) and white (n = 370) subjects from the Minnesota Heart Survey for whom lipoprotein levels were available. The mean high density lipoprotein-cholesterol level for black men in the sample (47 ± 1.5 mg/dl) was higher (P < 0.05) than that for white men (42 ± 0.9 mg/dl), while levels in women were not different between races. While the SacI and MspI markers at the apolipoprotein AI-CIII-AIV gene locus showed similar frequencies in blacks compared to whites, the degree of the linkage disequilibrium previously noted between these markers in white subjects was altered in blacks and the minor allele of the PstI marker at this locus was virtually absent in the black subjects (P < 0.005 vs whites). For black men, there were significant associations of the M2 allele and the S2M2 haplotype at the apolipoprotein AI locus with lower high density lipoprotein-cholesterol levels. The results are consistent with the hypothesis that DNA sequence variations in the vicinity of the apolipoprotein AI-CIII-AIV gene locus are associated with the difference in high density lipoprotein-cholesterol levels between blacks and whites. © 1992 Wiley-Liss, Inc.