Recent studies have suggested that pioglitazone exerts anti-oxidant properties which may countervail oxidative stress (OS). We aimed to elucidate the effects of pioglitazone on OS modulation and to compare its effects with metformin.Data from the randomized clinical trial (registration no.NCT01521624) were used. Newly diagnosed type 2 diabetes patients were assigned to pioglitazone 30mg daily (n=30), metformin 1000mg daily (n=50), or no medication (n=49). Recommendations for exercise and dietary modifications were provided for three groups. Serum concentrations of advanced oxidation protein products(AOPP), advanced glycation end products(AGE), ferritin reducing ability of plasma(FRAP), and enzymatic activities of paraoxonase(PON), lecithin-cholesterol asyltransferase(LCAT), and lipoprotein lipase(LPL) were measured at baseline and after three months.In comparison with no medication, pioglitazone proved to be superior in OS amelioration (p<0.05 in all analyses). Compared with metformin, both medications were equally effective in decrement of AOPP and AGE, along with increment of PON (p=0.688, 0.140, and 0.273, respectively). FRAP concentrations increased significantly with metformin (p=0.012). On the other hand, pioglitazone yielded better efficacy in restoration of LCAT and LPL enzymatic activities (p=0.037, and <0.001, respectively).Similar to metformin, three months treatment with Pioglitazone is beneficial in terms of OS alleviation and anti-oxidant capacity restoration.