Purpose We assessed the ability of Aliskiren (AL), a direct renin inhibitor, and Valsartan (VA), an angiotensin receptor blocker, to limit myocardial infarct size (IS) in mice with type-2 diabetes mellitus. Methods Db/Db mice, fed Western Diet, received 15-day pretreatment with: 1) vehicle; 2) AL 25 mg/kg/d; 3) AL 50 mg/kg/d; 4) VA 8 mg/kg/d; 5) VA 16 mg/kg/d; 6) AL 25+VA 16 mg/kg/d; or 7) AL 50+VA 16 mg/kg/d. Mice underwent 30 min coronary artery occlusion and 24 h reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC staining. Protein expression was assessed by immunobloting. Results IS in the control group was 42.9 +/- 2.1% of the AR. AL at 25 (21.9 +/- 2.9%) and 50 mg/kg/d (15.5 +/- 1.3%) reduced IS. VA at 16 mg/kg/d (18.8 +/- 1.2%), but not at 8 mg/kg/d (35.2 +/- 4.0%), limited IS. IS was the smallest in the AL50+VA16 group (6.3 +/- 0.9%). Both AL and VA reduced myocardial AT1R levels, without affecting AT2R levels, and increased the expression of Sirt1 and PGC-1 alpha with increased phosphorylation of Akt and eNOS. Conclusions AL, dose dependently limited myocardial IS in mice with type-2 diabetes mellitus. At doses shown to limit IS in non-diabetic animals, VA failed to reduce IS in Db/Db mice. However, at higher dose (16 mg/kg/d), VA reduced IS. Both drugs reduced the expression of AT1R and increased myocardial levels of the longevity genes Sirt1 and PGC-1 alpha along with increased Akt and eNOS phosphorylation.