Context: The link between C-reactive protein (CRP) and adiposity deserves to be further explored, considering the controversial diabetogenic role of CRP. Objective: We explored the potential causal role of CRP on measures of adiposity. Design: We used a Mendelian randomization approach with the CRP and LEPR genes as instrumental variables in a cross-sectional Caucasian population-based study comprising 2526 men and 2836 women. Adiposity was measured using body mass index (BMI), fat and lean mass estimated by bioelectrical impedance, and waist circumference. Results: Log-transformed CRP explained by the rs7553007 single-nucleotide polymorphism tagging the CRP gene was significantly associated with BMI regression coefficient: 1.22 (0.18; 2.25), P = 0.02 and fat mass 2.67 (0.65; 4.68), P = 0.01 but not with lean mass in women, whereas no association was found in men. Log-transformed CRP explained by the rs1805096 LEPR single-nucleotide polymorphism was also positively associated, although not significantly, with BMI or fat mass. The combined CRP-LEPR instrument explained 2.24 and 0.77% of CRP variance in women and men, respectively. Log-transformed CRP explained by this combined instrument was significantly associated with BMI 0.98 (0.32; 1.63), P = 0.004, fat mass 2.07 (0.79; 3.34), P = 0.001, and waist 2.09 (0.39; 3.78), P = 0.01 in women but not men. Conclusion: Our data suggest that CRP is causally and positively related to BMI in women and that this is mainly due to fat mass. Results on the combined CRP-LEPR instrument suggest that leptin may play a role in the causal association between CRP and adiposity in women. Results in men were not significant. Results in this study suggest that C-reactive protein is causally related to body mass index in women, and that this is mainly due to fat mass.