Primary osteoarthritis (OA) is a leading cause of disability in developed countries. Currently no satisfactory treatment to stop disease progression exists. Recent studies suggest that activation of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is an interesting therapeutic target for this disease. PPARγ is a transcription factor important for adipogenesis and adipocyte differentiation. Agonists of PPARγ inhibit inflammation and reduce generation of cartilage degradation products both in vitro and in vivo, and reduce the development/progression of cartilage lesions in OA animal models. However, there are no studies to assess the role of PPARγ in OA susceptibility of human peripheral joints in a Chinese population. We conducted a case-control study in a southeast Chinese population to determine the association of PPARγ gene polymorphisms (rs1801282, rs12629751, rs2292101, rs4135275 and rs1175543) with OA. One-hundred knee OA cases and 100 controls were studied. Statistically significant differences were detected in genotype and allele frequencies between OA and control groups in this population. For knee OA, the highest risk was associated with the variant allele T of the single nucleotide polymorphism rs12629751 (odds ratio (OR): 0.341, 95% confidence interval (CI):0.173-0.673, P = 0.002), and allele T of SNP rs12629751 (chi-square: 9.546, P = 0.002) could be considered as a risk factor of knee OA. Therefore, PPARγ mutation could be associated with the incidence of OA in a Chinese population. There is a significant association between the PPARγ polymorphism rs12629751 and susceptibility to knee OA in a southeast Chinese population.