Fibroblast growth factor 2 (FGF2) is cardioprotective in in vivo models of myocardial infarction; however, whether FGF2 has a protective role in in vivo ischemia-reperfusion (IR) injury, a model that more closely mimics acute myocardial infarction in humans, is not known. To assess the cardioprotective efficacy of endogenous FGF2, mice lacking a functional Fgf2 gene (Fgf2(-/-)) and wild-type controls were subjected to closed-chest regional cardiac IR injury (90 min ischemia, 7 days reperfusion). Fgf2(-/-) mice had significantly increased myocardial infarct size and significantly worsened cardiac function compared to wild-type controls at both 1 and 7 days post-IR injury. Pathophysiological analysis showed that at 1 day after IR injury Fgf2(-/-) mice have worsened cardiac strain patterns and increased myocardial cell death. Furthermore, at 7 days post-IR injury, Fgf2(-/-) mice showed a significantly reduced cardiac hypertrophic response, decreased cardiac vessel density, and increased vessel diameter in the peri-infarct area compared to wild-type controls. These data reveal both acute cardioprotective and a longer term proangiogenic potential of endogenous FGF2 in a clinically relevant, in vivo, closed-chest regional cardiac IR injury model that mimics acute myocardial infarction.