Reduced heart rate variability (HRV) and increased C-reactive protein (CRP) levels are both predictors of coronary artery disease and correlate with each other. We examined whether these 2 phenotypes share a common genetic substrate and investigated the relations of the CRP gene polymorphisms with both CRP levels and HRV indexes. We examined 236 male twins free of symptomatic coronary artery disease, with a mean age +/- SD of 54 +/- 2.9 years. The plasma CRP levels were measured and the frequency domain measures of HRV were assessed using a 24-hour electrocardiographic recording, including ultra-low-, very-low-, low-, and high-frequency power. Three single-nucleotide polymorphisms in the CRP gene were genotyped. Generalized estimating equations were used to examine the association between CRP and HRV, as well as the genotype-phenotype association. Bivariate structural equation modeling was performed to estimate the genetic and environmental correlations between CRP and HRV and the explanatory effect of CRP gene polymorphisms on the CRP-HRV association. Both CRP (h(2) = 0.76) and HRV indexes (h(2) = 0.56 to 0.64) showed high heritability. Greater CRP levels were significantly associated with lower HRV. A robust genetic correlation was found between CRP and ultra-low-frequency power (r(G) = -0.3, p = 0.001). One CRP single nucleotide polymorphism (rs1205) was significantly associated with both CRP (p = 0.003) and ultra-low-frequency power (p = 0.005) and explained 11% of the genetic covariance between them. In conclusion, reduced HRV correlates significantly with increased CRP plasma levels and this correlation is due, in large part, to common genetic influences. A polymorphism in the CRP gene contributes to both CRP levels and HRV.