We report a CNR1 haplotype (H3, frequency 21.1%) associated with fasting TG and HDL-C levels in 645 study subjects with class III obesity, nested within one of the largest population-based biobanks in the U.S. We localize the genetic effect to a single block of LD containing the CNR1 coding region, and we demonstrate that this effect is only partly dependent upon nutrient intake and physical activity. Here, CNR1 is linked to obesity disorder.