To investigate the influence of peroxisome proliferator-activated receptor γ2 (PPAR-γ2) gene polymorphism rs1801282 and protein tyrosine phosphatase receptor type D (PTPRD) gene polymorphism rs17584499 on the occurrence of type 2 diabetes and pioglitazone efficacy in a Chinese Han population.One hundred ninety seven type 2 diabetes patients and 212 healthy controls were enrolled. Among them, 67 type 2 diabetes patients were administered pioglitazone (30 mg/d, po) for 3 months. All the subjects were genotyped for genetic variants in PPAR-γ2 and PTPRD using MALDI-TOF mass spectrometry. Fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, serum triglyceride, total cholesterol, low-density and high-density lipoprotein-cholesterol were determined.The PPAR-γ2 gene rs1801282 polymorphism was significantly associated with type 2 diabetes susceptibility (OR=0.515, 95% CI 0.268-0.990) and the PTPRD gene rs17584499 polymorphism was also significantly associated with type 2 diabetes (OR=1.984, 95% CI 1.135-3.469) in a dominant model adjusted for age, gender and BMI. After pioglitazone treatment for 3 months, the type 2 diabetes patients with PPAR-γ2 rs1801282 CG genotypes significantly showed higher differential values of postprandial plasma glucose and serum triglyceride compared with those with rs1801282 CC genotype. The patients with PTPRD rs17584499 CT+TT genotypes showed significantly lower differential value of postprandial plasma glucose compared to those with rs17584499 CC genotype.Diabetes risk alleles in PPAR-γ2 (rs1801282) and PTPRD (rs17584499) are associated with pioglitazone therapeutic efficacy.