We investigated whether an association exists between genetic variants of the human obesity (OB or leptin) gene and body mass index (BMI) or weight in subjects with Prader-Willi syndrome (PWS) and in age- and gender-matched lean and obese subjects without PWS. The study included 51 subjects with PWS (mean age = 17.7 ± 9.5 years, BMI = 29.7 ± 8.3 kg/m2); 50 non-PWS obese subjects (mean age = 18.2 ± 10.8 years, BMI = 33.3 ± 9.5 kg/m2); and 53 non-PWS lean subjects (mean age = 17.8 ± 9.5 years, BMI = 19.5 ± 2.9 kg/m2). Allele sizes were determined via standard polymerase chain reaction of the D7S1875 locus, a dinucleotide repeat polymorphism close to the OB gene and classified as trichotomous (homozygous < 208 bp, heterozygous < 208/ ≥ 208 bp, homozygous ≥ 208 bp) or dichotomous (homozygous < 208 bp or not). Non-PWS males showed a marked decrease in weight with larger alleles while females did not (interaction effect, p < 0.05). Comparable effects were not observed among the PWS subjects. Associations between BMI and genotype were statistically significant (r = 0.22, one-tailed p < 0.05) and comparable to previous research among the non-PWS subjects < 18 years, but not the adults (r = 0.05, one-tailed p = 0.38). Correlations were not statistically significant among either the adult or non-adult PWS subjects.