A random sample of 290 white men was examined for association between restriction fragment length polymorphism (RFLP) haplotypes (closely linked RFLPs on a single chromosome) of the apolipoprotein-B gene and serum levels of cholesterol, triglyceride, and high-density lipoprotein, obesity, smoking, alcohol consumption, and coronary heart disease. Haplotype or single RFLP frequencies differed significantly for obesity (p less than 0.005), serum cholesterol (p less than 0.005), and coronary heart disease (p less than 0.05), but for no other variable. Obesity was associated with haplotypes involving minimum PvuII and XbaI RFLPs are likely to be in linkage disequilibrium with nearby functional variation predisposing to obesity. Significant variation in serum cholesterol levels was associated with three functional alleles defined by MspI and EcoRI RFLP pairs (p less than 0.03). These RFLPs correspond to charged aminoacid variants at positions 3611 (arginine to glutamine) and 4154 (glutamic acid to lysine), which lie near the low-density-lipoprotein (LDL) receptor binding region of apolipoprotein-B. The three alleles showed stratification of serum cholesterol between low, normal, and high levels. Coronary heart disease was associated with minimum haplotypes involving XbaI and MspI RFLPs. Together these results suggest that inherited variations of the apolipoprotein-B gene, probably in the form of charged aminoacid substitutions, influence circulating cholesterol concentration, and that these and other functional variants of the apolipoprotein-B gene affect susceptibility to coronary heart disease and obesity.