We sought to investigate whether genetic variability within the CRP gene affects CRP levels. C-reactive protein (CRP), an acute-phase reactant in inflammation, is an important predictor for cardiovascular disease. The genetic determinants of plasma CRP level remain unknown. We assessed the genotypes of two common polymorphisms within the CRP gene, an exonic 1059G > C and an intronic T > A base substitution, among 2397 participants of a community-based study; 1334 had no prior cardiovascular history, while 1063 had a prior cardiovascular history. Univariable and multivariable-adjusted analyses were performed to examine the association of CRP polymorphisms with CRP levels, modeling different modes of inheritance. The genetic polymorphisms were significantly associated with baseline CRP levels in univariable analysis (1059G > C: GG versus GC or CC genotypes, median CRP levels 0.22 versus 0.15 mg/L, P < 0.0001; intronic T > A: TT versus AT versus AA genotypes, median CRP levels 0.19 versus 0.23 versus 0.24 mg/L, P = 0.003). This relationship persisted after adjusting for age, sex, body mass index, ethnicity, hypertension, smoking, diabetes, hyperlipidemia, and aspirin use. Furthermore, these effects were present in subgroup analyses limited to those with and without prevalent coronary disease, and when assessed within Caucasians only. The present data provide evidence of a genetic component of CRP levels, independently of traditional risk factors for cardiovascular disease. Whether genetic markers can add to information yielded by high sensitivity CRP (hsCRP) in assessing cardiovascular risk needs further evaluation.