Objective. Several studies suggest that bone mineral density (BMD) is reduced in chronic inflammatory diseases. Higher serum levels of C-reactive protein (CRP) have been associated with lower BMD in women and older adults. However, it is not clear whether this association holds in a representative sample of the general population. The purpose of this study was to examine the relationship between BMD and CRP level in a large representative US population-based sample from the National Health and Nutrition Examination Survey (NHANES).Methods. We included participants age >20 years with BMD (total and subregions) measured by dual x-ray absorptiometry scans and complete information on covariates from NHANES. The association between CRP level and BMD was evaluated using multivariate linear regression models, adjusting for potential confounders and further adjusting for comorbid diseases, medications, and serum vitamin D levels.Results. The study sample included 10,475 participants (53% Caucasian, 22% Mexican American, 18% African American, and 7% other races). Men had higher BMD and lower CRP concentrations than women. BMD (total body BMD as well as subtotal BMD and BMD of the extremities, ribs, and trunk subregions) was inversely associated with quintiles of CRP concentration both in men and in women in a dose-dependent manner (for total BMD, P for trend < 0.0001 for men, P for trend ؍ 0.0005 for women). The associations were independent of medications, comorbidities, and other potential confounders. The results remained largely unchanged with further adjustment for serum vitamin D levels.Conclusion. Among men and women in a large representative population-based sample, the CRP level was inversely and independently associated with total BMD in a dose-dependent manner.