Several studies have suggested that an increased high sensitivity C-reactive protein (hsCRP) level is a strong independent predictor of increased risk for atherosclerotic cardiovascular mortality and morbidity. Reduced heart rate variability (HRV) has also been reported to predict cardiovascular events such as sudden death and myocardial infarction in apparently healthy subjects. The aim of this cross-sectional study was to test the possible correlation between variation of the R-R interval as one of the markers of HRV and serum hsCRP levels in a general population in Japan. Resting, supine, 2-minute, beat-to-beat heart rate data were collected in 823 randomly selected participants enrolled in our cohort study. The coefficient of variation of the R-R interval (CVrr) was obtained as a parameter of HRV. To determine which factors predict the presence of low CVrr (below the 5 percentile) in this group, we performed a multivariate logistic regression analysis using cardiovascular risk factors and an elevated hsCRP level as independent variables. The lowest CVrr group showed significantly higher hsCRP levels compared to those of other quartiles (P < 0.01). After adjustment for confounding factors such as age, heart rate, obesity, hypercholesterolemia, and hypertension by multivariate logistic analysis, an elevated hsCRP level (OR = 3.11, 95%CI; 1.27-7.60: P < 0.02) was a significant independent predictor of low CVrr. The results of the present study indicate that an increased serum hsCRP level is significantly associated with reduced CVrr in this general population. It is conceivable that the parasympathetic nerve withdrawal and inflammation could interact with each other, resulting in the progression of atherosclerotic cardiovascular disease.