Thiazolidinediones (TZDs) include a group of antihyperglycemic agents that enhance insulin sensitivity and reduce insulin resistance at sites of insulin action specifically skeletal muscles, liver and adipose tissue. In September 2010, the FDA has launched a safety review of pioglitazone citing preliminary epidemiologic evidence suggesting that pioglitazone may be linked to a higher risk for bladder cancer. Bladder tumors were seen in male rats receiving a clinical dose of pioglitazone. Also, in 2 clinical studies, patients receiving pioglitazone experienced a higher rate of bladder cancer than patients taking other agents (Lewis et al., 2008). In this study, the genotoxic and cytotoxic potential of pioglitazone (20, 40 and 80mg/kg, orally daily for 4 weeks) was evaluated against the nicotinamide (230mg/kg) and streptozotocin (65mg/kg) induced somatic and germinal cells defect using a battery of in vivo cytogenetic assays such as the micronucleus, chromosome aberration, mitotic index and sperm abnormality test in male Wistar rats. The obtained results demonstrated that pioglitazone significantly reduced the diabetes-induced genetic damage in both somatic and germinal cells and improved the cell proliferation changes in somatic cells which was attributed to its antioxidant properties. A significant elevation, however, in polyploidy was noticed in the diabetic rats treated with 80mg/kg of pioglitazone. As numerical chromosomal aberrations have also been associated with tumorigenesis, this observation suggests a possible genotoxic effect of pioglitazone when used for a long period in treating diabetes.