Objective: Glucagon-like peptide-1 (7-36)amide (GLP-1) is cleaved by dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9-36)amide. We examined whether chemical inhibition or genetic elimination of DPP-4 activity affects cardiovascular function in normoglycemic and diabetic mice after experimental myocardial infarction. Research design and methods: Cardiac structure and function was assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout (Dpp4(-/-)) mice versus wild-type (Dpp4(+/+)) littermate controls and after left anterior descending (LAD) coronary artery ligation-induced myocardial infarction (MI). Effects of sustained DPP-4 inhibition with sitagliptin versus treatment with metformin were ascertained after experimental MI in a high-fat diet-streptozotocin model of murine diabetes. Functional recovery from ischemia-reperfusion (I/R) injury was measured in isolated hearts from Dpp4(-/-) versus Dpp4(+/+) littermates and from normoglycemic wild-type (WT) mice treated with sitagliptin or metformin. Cardioprotective signaling in the murine heart was examined by RT-PCR and Western blot analyses. Results: Dpp4(-/-) mice exhibited normal indexes of cardiac structure and function. Survival post-MI was modestly improved in normoglycemic Dpp4(-/-) mice. Increased cardiac expression of phosphorylated AKT (pAKT), pGSK3beta, and atrial natriuretic peptide (ANP) was detected in the nonischemic Dpp4(-/-) heart, and HO-1, ANP, and pGSK3beta proteins were induced in nonischemic hearts from diabetic mice treated with sitagliptin or metformin. Sitagliptin and metformin treatment of wild-type diabetic mice reduced mortality after myocardial infarction. Sitagliptin improved functional recovery after I/R injury ex vivo in WT mice with similar protection from I/R injury also manifest in hearts from Dpp4(-/-) versus Dpp4(+/+) mice. Conclusions: Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.