Background Moderately elevated serum C-reactive protein (CRP) concentration is a systemic marker of inflammation and a documented risk factor for cardiovascular disease in otherwise healthy persons. Unrecognized infections, such as periodontal disease, may induce an acute-phase response, elevating CRP levels. We evaluated the association between periodontal disease and CRP levels in adults in the Atherosclerosis Risk in Communities study. Methods Oral examinations were conducted between January 1, 1996, and December 31, 1998, on 5552 ARIC participants (aged 52-74 years) from 4 US communities. Periodontal disease was quantified as the percentage of periodontal sites with pocket depth of 4 mm or more. Serum CRP concentration was quantified in milligrams per liter using an enzyme-linked immunosorbent assay. Results Mean (SE) CRP level was 7.6 (0.6) mg/L among people with extensive periodontal pockets (>30% of sites with pocket depth ≥4 mm), approximately one-third greater than that for people with less extensive periodontal pockets (5.7 [0.1] mg/L). In a multivariable linear regression model that controlled for age, sex, diabetes mellitus, cigarette use, and nonsteroidal anti-inflammatory drug use, the association of extensive periodontal pockets with CRP concentration was modified by body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters). For people with a BMI of 20, the model predicted a 2-fold difference in mean CRP concentration between periodontal pocket groups (7.5 vs 3.6 mg/L), but the difference decreased with increasing BMI and was negligible when BMI equaled 35. Conclusions Extensive periodontal disease and BMI are jointly associated with increased CRP levels in otherwise healthy, middle-aged adults, suggesting the need for medical and dental diagnoses when evaluating sources of acute-phase response in some patients.