INTRODUCTION: An imbalance between reactive oxygen species (ROS) generation and the defence mechanisms underlying the activity of antioxidant enzymes has been demonstrated as the leading pathology in diabetes mellitus (DM)-related microvascular complications. PURPOSE: This study aims to evaluate the association between polymorphisms in antioxidant enzyme-encoding genes: catalase (CAT); manganese superoxide dismutase (Mn-SOD); glutathione S transferase M1 (GSTM1); and GSTT1 glutathione S transferase T1 (GSTT1), and the risk of type II diabetic nephropathy (DN) in the Saudi population. PATIENTS AND METHODS: The present study involved 64 type II DM patients with nephropathy and 64 type II diabetes patients without nephropathy from the King Abdulaziz University (KAU) Hospital. They underwent real-time PCR genotyping for the Mn-SOD and CAT genes. Multiplex PCR was used to detect GSTM1- and GSTT1-null polymorphisms. RESULTS: A statistically significant difference was observed between the case and control groups with regard to polymorphisms in the CAT gene (P = 0.037), but not for polymorphisms in the Mn-SOD (P = 0.64) gene. In addition, a statistically significant association was observed between null polymorphisms of the GSTT1 and GSTM1 genes and DN in the case and control groups (P = 0.046 and P = 0.035, respectively). CONCLUSION: Our results showed that the genetic ability to combat oxidative stress may play a major role in DN pathogenesis in Saudi type II DM patients. These polymorphisms in antioxidant enzyme-encoding genes could be used as independent genetic markers for the construction of risk prediction models for kidney-related complications in type II DM patients.