Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor-based incretin therapy intended for the treatment of type 2 diabetes mellitus (T2DM), has not been linked to adverse effects on the pancreas in prospective clinical trials or in nonclinical toxicology studies. To further assess potential pancreatic effects, sitagliptin was studied in the male Zucker diabetic fatty (ZDF) rat model of T2DM. Following 3 months of oral dosing with vehicle, or sitagliptin at doses 3- to 19-fold above the clinically therapeutic plasma concentration, which increased active plasma glucagon-like peptide-1 levels up to approximately 3-fold, or following 3 months of oral dosing with metformin, a non-incretin-based reference T2DM treatment, the pancreas of male ZDF rats was evaluated using qualitative and quantitative histopathology techniques. In the quantitative evaluation, proliferative index was calculated in exocrine pancreatic ducts and ductules using computer-based image analysis on sections stained by immunohistochemistry for cytokeratin (a cytoplasmic epithelial cell marker) and Ki-67 (a nuclear marker of recent cell division). Relative to controls, sitagliptin treatment did not alter disease progression based on detailed clinical signs and clinical pathology assessments. Sitagliptin treatment did not result in pancreatitis or any adverse effect on the pancreas based on a qualitative histopathology evaluation. Proliferative index did not increase with sitagliptin treatment based on quantitative assessment of more than 5000 sections of pancreas, where control group means ranged from 0.698-0.845% and sitagliptin-treated group means ranged from 0.679-0.701% (P = .874). Metformin treatment was similarly evaluated and found not to have adverse effects on pancreas.