CONTEXT: The endocannabinoid system modulates food intake and body weight in animal models. Treatment with the cannabinoid type 1 receptor blocker, rimonabant, reduces body weight in obese individuals. OBJECTIVE: The aim of this study was to determine whether single nucleotide polymorphisms of the gene encoding cannabinoid type 1 receptor, CNR1, are associated with body fat mass and distribution in two independent samples of white European adult men. DESIGN, SETTING, AND PARTICIPANTS: The 3813A/G and 4895A/G single nucleotide polymorphisms at the exon 4 of CNR1 were genotyped in 930 participants to the Olivetti Prospective Heart Study (OPHS) in Southern Italy and in 216 participants to the Wandsworth Heart and Stroke Study in the United Kingdom. Retrospective analysis was also performed on an OPHS subsample (n = 360) for which anthropometric data from 1987 and 1994-1995 examinations were available. MAIN OUTCOME MEASURES: CNR1 genotypes and anthropometric measures of body fat distribution were determined. RESULTS: In the OPHS study, the 3813G allele was associated with increased subscapular skinfold thickness (24.2 +/- 9.1 vs. 22.8 +/- 7.7 mm; P = 0.031) and waist circumference (WC) (99.1 +/- 8.8 vs. 97.7 +/- 8.8 cm; P = 0.050). No association was observed with 4895A/G variant. Haplotype analysis confirmed that the unique haplotype carrying the 3813G was associated with increased WC and subscapular skinfold thickness. Similar results were observed in the OPHS retrospective subsample and the Wandsworth Heart and Stroke Study sample. In the latter, the 3813G was associated with increased WC (96.8 +/- 11.3 vs. 91.6 +/- 10.4 cm; P = 0.006). CONCLUSIONS: Genetic variants at CNR1 are associated with obesity-related phenotypes in men. The detection of polymorphic variants in genes involved in the process of fat accumulation may help identify specific targets for pharmacological treatment of obesity and related metabolic abnormalities.