Peroxisome proliferation-activated receptor-gamma2 (PPARgamma2) is exclusively expressed in adipose tissue and belongs to the transcriptional regulators of adipocyte differentiation. Recently, two missense single-point mutations have been described in the PPARgamma2 gene: Pro12Ala and Pro115Gln. It was our aim to determine the frequency of these polymorphisms in a Caucasian cohort and to investigate their possible role in the pathogenesis of obesity, type 2 diabetes, and related metabolic disorders. The genotypes of 359 subjects (149 males, 210 females) with varying degrees of obesity and with or without type 2 diabetes were determined. Subsequent to genomic polymerase chain reaction amplification, the HpaII restriction fragment length polymorphism (RFLP) analysis and the HindII RFLP analysis were used for genotyping the Pro12Ala and Pro115Gln polymorphism, respectively. For the Pro115Gln polymorphism, all 359 subjects showed wild-type sequence, emphasizing the very rare occurrence of the mutated allele. For the Pro12Ala polymorphism, 276 subjects (76.9%) were homozygous for the wild-type allele, 80 (22.3%) were heterozygous, and only 3 (0.8%) were homozygous for the mutated allele. Genotype frequency was calculated to be 0.88 for the wild-type allele and 0.012 for the mutated allele. No significant differences were found in age; gender; body mass index; total cholesterol; low-density, high-density, and very low density lipoproteins; triglycerides; Lp(a); uric acid; and diabetes manifestation by comparing the different genotypes. Therefore, a major role of these polymorphisms in the pathogenesis of obesity and diabetes can be excluded.