Background: Type 2 diabetes mellitus (DM) is a progressive chronic disorder that necessitates appropriate treatment and management in order to prevent complications. Thiazolidinediones such as pioglitazone and Dipeptidyl peptidase-4 inhibitors (DPP4i) such as sitagliptin have recently been used for type 2 DM control. The aim of this study was to compare the effects of sitagliptin or pioglitazone on the treatment of diabetic patients with poor control of glycemic status following metformin and sulfonylurea administration. Methods & Materials: In this randomized clinical trial, 90 patients with uncontrolled type 2 DM under treatment with full-dose metformin (1500 to 2000 mg/day) and sulfonylureas (glibenclamide 15 to 20 mg/day) were enrolled. The patients were allocated into two groups with equal numbers. One group received a single dose of pioglitazone (30 mg/day) and the other received a single dose of sitagliptin (100 mg/day) as the third medication. Fasting blood sugar (FBS), two hours postprandial blood sugar (2hpp), and HbA1c were assessed before and after three months of treatment. Results: FBS level in the sitagliptin group was higher than the pioglitazone group; however, this difference was not statistically significant (131.27 ± 39.18 versus 123.47±36.73, p=0.234, respectively). No significant differences were also observed in HbA1c (7.18±0.86 versus 7.23±1.03, p=0.572, respectively) and 2hpp (193.56±63.02 versus 198.58±51.5, p=0.992, respectively) after treatment between sitagliptin and pioglitazone groups. Mean weight in the sitagliptin group was lower compared to the pioglitazone group after treatment, however, this difference was not statistically significant (p=0.902). Conclusion: Both sitagliptin and pioglitazone as a third oral agent had similar efficacy in the control of the glycemic state. Considering the possible higher risk of weight gain after pioglitazone treatment, sitagliptin administration especially in overweight type 2 DM patients with poor glycemic control may be beneficial rather than the other oral agents.