Pharmacologic blockade of the endocannabinoid receptor 1 leads to weight loss and an improved metabolic risk profile in overweight and obese individuals. We hypothesize that common genetic variants in the CNR1 (encoding endocannabinoid receptor 1) and FAAH genes (encoding fatty acid amide hydrolase, a key enzyme hydrolyzing endocannabinoids) are associated with adiposity traits. We genotyped 18 single-nucleotide polymorphisms (SNPs) in the CNR1 gene and 9 SNPs in the FAAH gene in 2,415 Framingham Offspring Study participants (mean age 61 +/- 10 years; 52.6% women; mean BMI 28.2 +/- 5.4 kg/m(2); 30.3% obese) and studied them for association with cross-sectional and longitudinal measures of adiposity (BMI, waist circumference, change over time in BMI and waist circumference, visceral and subcutaneous adipose tissue) using linear mixed-effect models. The selected SNPs captured 85% (r(2) = 0.8) of the common variation (minor allele frequency >5%) at the CNR1 locus and 96% (r(2) = 0.8) of the common variation at the FAAH locus (defined as the genomic segment containing the gene +20 kb upstream and +10 kb downstream). After correction for multiple testing, none of the SNPs in the CNR1 gene or in the FAAH gene displayed statistical evidence for association with BMI, waist circumference, and visceral adipose tissue or subcutaneous adipose tissue (all P > 0.18). Despite comprehensive SNP mapping across the genes and their regulatory regions in a large unselected sample, we failed to find evidence for an association of common variants in the CNR1 and FAAH genes with measures of adiposity in our community-based sample.