OBJECTIVE—To investigate the influence of peroxisome proliferator-activated receptor-γ (PPAR-γ) gene variants on the response rate to therapy with the thiazolidinedione (TZD) pioglitazone, because in vitro studies have suggested that genetic variants of the PPAR-γ gene may influence the drug efficacy of TZD. RESEARCH DESIGN AND METHODS—A total of 131 patients were treated in an open-label, randomized, multicenter study with pioglitazone (45 mg o.d.) during a course of ≥26 weeks. Response to the pioglitazone therapy was defined by either a >20% decrease in fasting plasma glucose or a >15% decrease in HbA1c values after 26 weeks of pioglitazone treatment. We evaluated the association between the PPAR-γ genotype and the response rate to pioglitazone treatment. RESULTS—The Pro12Ala and the Pro12Pro variants in the PPAR-γ gene are not associated with the response rate to pioglitazone treatment in patients with type 2 diabetes. However, we identified initial fasting plasma glucose level >11.0 mmol/l, HbA1c value >9.0%, BMI >32 kg/m2, and fasting C-peptide concentrations at baseline >2.5 pmol/l as predominant confounding factors for the responder frequency to pioglitazone treatment. CONCLUSIONS—The Pro12Ala variant in the PPAR-γ gene does not affect the therapy efficacy of pioglitazone, suggesting that the drug-treatment response is independent from pharmacogenetic effects between PPAR-γ and its ligand pioglitazone. Whether the Ala12Ala genotype plays a role in the response rate to TZD therapy remains to be determined.