Several combination therapies have been investigated in an effort to achieve and maintain glycemic control in patients with type 2 diabetes. In this study, we combined the novel dipeptidyl peptidase (DPP)-IV inhibitor ASP8497 with the antidiabetic drugs metformin, glibenclamide, voglibose, rosiglitazone, and insulin to examine the effects of each combination on glucose tolerance in streptozotocin-nicotinamide-induced mildly diabetic mice. Single treatments with ASP8497 (1 mg/kg), metformin (300 mg/kg), glibenclamide (3 mg/kg), voglibose (0.3 mg/kg), rosiglitazone (10 mg/kg), or insulin (0.2 IU/kg) significantly improved glucose tolerance during the liquid meal tolerance test. In addition, combination treatment with ASP8497 and each antidiabetic drug additively improved glucose tolerance. Among these, the combination of ASP8497 and glibenclamide or insulin additively ameliorated glucose tolerance with an additive increase in the plasma insulin level; however, it did not affect the fasting blood glucose lowering effects of glibenclamide or insulin. These profiles indicate that the combination of ASP8497 with existing antidiabetic drugs could be useful for correcting the postprandial hyperglycemia seen with type 2 diabetes.