Abstract Body: Background: Ketones may have beneficial impacts on cardiovascular outcomes. We assessed the impact of endogenously produced ketones versus exogenous ketone administration on outcomes following myocardial infarction (MI) in male and female mice. Methods: Ketones were endogenously elevated by feeding adult C57BL/6J mice a ketogenic diet (KD; 80% fat/20% protein) for 8 weeks prior to MI, while control (ctrl) mice were fed standard chow diet. To exogenously increase ketones, mice were administered 1,3-butanediol (BD) at either 10% (BD10) or 20% (BD20) volume in the drinking water for 8 weeks. MI was induced by surgical ligation of the left coronary artery in adult C57BL/6J mice. Ultrasound echocardiography was performed to assess left ventricular (LV) function at day 7 post-MI and mice were euthanized. Results: BD10, BD20, and KD all significantly increased blood ketones at the time of MI. BD20 significantly increased mortality after MI in males (29% vs 44% ctrl) and females (58% vs 100% ctrl). KD modestly improved survival after MI in males (58% vs 44% ctrl), decreased infarct size (40% LV area vs 48% ctrl, p=0.01), reduced LV dilation (end-diastolic volume; 135µL vs 158µL ctrl; p=0.04), attenuated wall thinning (increased posterior wall thickness; 0.51mm vs 0.34mm ctrl; p=0.02), and improved ejection fraction (15% vs 11%, p=0.001). Flow cytometry analysis demonstrated that KD decreased total CD45+ immune cells in male (p=0.003) and female (p=0.0006) infarcted hearts, and decreased Ly6G+ neutrophils (p=0.001) and CD11b+Ly6G-F4/80-low (i.e. non-resident macrophages, p=0.046) in males. KD also reduced macrophages in male spleens (CD11b+Ly6G-). By quantitative PCR analysis, KD significantly decreased Ccl7 mRNA (1.6-fold decrease, p=0.006) and increased Tgfb1 mRNA (1.5-fold increase, p=0.0009). Conclusions: Ketogenic diet, but not butanediol, improves post-MI outcomes particularly in adult male mice, which may be due to attenuated inflammatory responses.