Obese subjects have higher circulating levels of C-reactive protein (CRP) than normal subjects, and it has been shown that CRP per se may contribute to atherogenesis. The mechanism linking increased fat mass with high CRP levels has not been exhaustively explained. It has been suggested that adipose tissue-produced cytokines, including interleukin-6, tumor necrosis factor-alpha, and interleukin-1beta, represent the causal link between increased body fat and high CRP levels. It has been hypothesized that the hormone leptin, released by fat cells, may stimulate CRP production independent of cytokines. This study measured circulating leptin, CRP, interleukin-6, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-8 in 946 community-dwelling older subjects (398 men, 548 women; age range 65 to 102 years) enrolled in a large population-based study. Confounders included demographics, functional, cognitive and affective status, diet and lifestyle, body composition, drugs, and chronic diseases. A direct association was found between leptin and CRP (p = 0.004), independent of cytokines and other possible confounders. The association was stronger in younger than in older subjects but was not influenced by gender or body mass index. In conclusion, these findings suggest that leptin may directly stimulate the production of CRP independent of fat-cell produced cytokines in older adults.