Obesity has a strong genetic etiology involving numerous identified metabolic pathways and others not yet examined. We investigated the association between severe obesity and genetic variation in selected candidate genes, including three drug-related genes: cannabinoid receptor 1 (CNR1), N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), and gastric lipase (LIPF); and three genes related to inflammation: nicotinamide phosphoribosyltransferase, six-transmembrane epithelial antigen of the prostate 4 (STEAP4) and interleukin 18 (IL-18). Subjects were 1,632 individuals with severe obesity (BMI ≥ 35 kg/m²) and 3,379 controls (BMI 20-24.9 kg/m²) that took part in a Norwegian population based cohort study. Tagging single-nucleotide polymorphisms (SNPs) of the coding region of these genes were analyzed. SNP-haplotypes for each gene were constructed in order to analyze allelic, genotypic, and haplotypic association to obesity. A single SNPs rs17605251 in NAPEPLD was nominally associated with BMI ≥ 35 kg/m² (P = 0.035). A common haplotype in NAPEPLD was associated with BMI ≥ 35 kg/m² after correction for multiple testing. The allele frequency was 56.8% in cases and 60.3% in controls, giving an odds ratio (OR) of 0.87 (95% confidence interval (CI) 0.79, 0.95; P = 0.0016). Homozygosity for this haplotype was protective against obesity (OR 0.79 (CI 0.70-0.91); P = 0.00059). The SNP rs7913071 in LIPF was associated with obesity, but the association lost statistical significance after correction for multiple testing. The CNR1, IL-18, STEAP4, and nicotinamide phosphoribosyltransferase genes were not associated with obesity. In conclusion a common haplotype in NAPEPLD, an enzyme involved in endocannabinoid synthesis, was protective against obesity.