Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Glucagon-like peptide-1 has been reported to increase islet cell proliferation and reduce apoptosis of β-cells in rodents. In this study, we explored the effect of chronic administration of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, β-cell function, and β-cell mass in Irs2-knockout (Irs2−/−) mice. Wild-type and Irs2−/− mice were fed a high-fat diet for 20 wk, with or without vildagliptin. In both genotypes of mice, vildagliptin significantly decreased the area under the curve (0–120 min) of blood glucose and increased the insulin response to glucose during the oral glucose tolerance test. In the oral glucose tolerance test performed 1 d after discontinuation of vildagliptin administration, the area under the curve (0–120 min) of blood glucose was still significantly decreased and the insulin response to glucose was significantly increased in the Irs2−/− mice treated with vildagliptin as compared with the values in the mice not treated with vildagliptin. Histochemical analysis of the pancreatic islets revealed significant increase of the β-cell mass and decrease in the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive β-cells but no significant increase of the bromodeoxyuridine incorporation in Irs2−/− mice treated with vildagliptin. Our results suggest that vildagliptin improved glucose tolerance and increased the β-cell mass by reducing β-cell apoptosis in the Irs2−/− mice, and that the reduction of β-cell apoptosis by vildagliptin was independent of the Irs2 expression in the cells.