Elevation of baseline C-reactive protein (CRP) is associated with increased risk of cardiac disease. This increase might reflect low-grade inflammation, but differences in CRP serum levels might also have a genetic component. To test this possibility, we investigated whether a polymorphic GT-repeat in the intron of the CRP gene contributes to variation in baseline CRP. We found that the polymorphism was associated with differences in baseline CRP in both normal individuals and in patients with the inflammatory disease systemic lupus erythematosus, viz. donors carrying two GT 16 alleles, two GT 21 alleles, or GT 16/21 heterozygotes had two-fold lower serum CRP than those with other genotypes. The frequency of GT 16 and GT 21 was two-fold higher in Caucasians than in African-Americans, but there was no difference in allele distribution between patients and controls. It is not yet known how this genetic polymorphism mediates its effect on CRP expression, and it probably is not a systemic lupus erythematosus susceptibility factor. Rather, the CRP intron polymorphism likely modifies the disease phenotype. On the other hand, the fact that baseline CRP does have a genetic component suggests that in coronary disease, stratification of risk assessment based on CRP levels might be enhanced by consideration of this polymorphism.