We examined the effect of fibroblast growth factor-2 (FGF-2) on myocardial resistance to injury when administered after the onset of ischemia, in vivo and ex vivo, and the role of FGF-2 receptors and protein kinase C (PKC). FGF-2 was injected into the left ventricle of rats undergoing permanent surgical coronary occlusion leading to myocardial infarction (MI). After 24 hours, FGF-2-treated hearts displayed significantly reduced injury, determined by histological staining and troponin-T release, and improved developed pressure, compared to untreated controls. An FGF-2 mutant with diminished affinity for the tyrosine kinase FGF-2 receptor 1 (FGFR1) was not cardioprotective. FGF-2-treated hearts retained improved function and decreased damage at 6 weeks post-MI. In the ex vivo heart, FGF-2 administration during reperfusion after 30 min ischemia improved functional recovery and increased relative levels of PKC subtypes ,, in the particulate fraction, in a chelerythrine-preventable mode; it also decreased loss of energy metabolites. We conclude that intramyocardial FGF-2 administration shortly after the onset of ischemia confers protection from acute and chronic cardiac dysfunction and damage; FGF-2 delivered during reperfusion protects from ischemia-reperfusion injury; protection by FGF-2 requires intact binding to FGFR1, and is likely mediated by PKC.