A genetic link between lipid metabolism and inflammation has been suggested by the association between variation in the APOE gene and plasma C-reactive protein (CRP). This association was confirmed among Caucasians and extended to an African-American population, and the well-known associations of APOE variation with LDL-C and apoE protein were also observed. While eight common variants in APOE were examined, the association with CRP involved primarily the two nonsynonymous SNPs that define the major epsilon2, epsilon3, and epsilon4 alleles. In particular, the strongest link involved lower CRP levels among carriers of the APOE epsilon4 allele that also contributes to the risk of cardiovascular and Alzheimer's diseases as well as to higher lipid levels. A lesser effect was characterized by lower CRP levels among carriers of a subtype of the epsilon3 allele. The magnitude of the association with plasma CRP was at least as great as the effect of variation in the CRP gene itself. Quantitative analysis suggested that the effect on CRP is more likely a consequence of intrinsic functional differences among the E2, E3, and E4 apoE proteins than different levels of apoE protein or LDL-C in the plasma.