Objective. The serum C-reactive protein (CRP) concentration is commonly used in rheumatoid arthritis (RA) as a surrogate marker of systemic inflammation, presumably induced by synovitis. However, other tissues, such as adipose tissue, can induce CRP production. This study was undertaken to explore the associations between measures of adiposity and CRP levels in RA. Methods. One hundred ninety-six men and women with RA underwent anthropometric assessment and total body dual-energy x-ray absorptiometry for measurement of total and regional body fat and lean mass. The associations between measures of fat and lean mass and serum levels of CRP and interleukin-6 (IL-6) were determined in analyses stratified by sex, with adjustment for pertinent demographic, lifestyle, and RA disease and treatment covariates as well as for the potential modifying effects of articular activity and biologic pharmacotherapeutic agents. Results. All measures of adiposity were significantly associated with the level of CRP in women, but not in men. In women, the measure of adiposity that showed the strongest association with the CRP level was truncal fat, in which, in adjusted analyses, each kilogram increase was associated with a 0.101-unit increase in the logarithmically transformed CRP level (P < 0.001). Neither the level of articular activity nor the use of biologic agents significantly modified this association in women. However, in men, elevated articular involvement was associated with a decreasing CRP level as truncal fat increased. For all analyses, substitution of IL-6 for CRP produced similar findings. Conclusion. Adiposity is independently associated with CRP levels in women with RA, and thus may confound the estimation of RA disease activity when serum CRP concentration is used as a surrogate for systemic inflammation. © 2008, American College of Rheumatology.