Background: The activation of the epidermal growth factor family of receptors may improve cardiac protection after injury. One epidermal growth factor family ligand, transforming growth factor-alpha, promotes wound healing in multiple tissues in response to oxidative injury and might confer resistance to myocardial depressant factors, although the role of transforming growth factor-alpha in myocardial ischemia/reperfusion injury is unknown. We hypothesized that preischemic infusion of transforming growth factor-alpha would improve myocardial functional recovery after acute ischemia/reperfusion. Methods: The hearts from adult male rats were isolated and perfused via the Langendorff model. Immediately prior to ischemia, the hearts received an intracoronary infusion of either vehicle or transforming growth factor-alpha (1 ng, 10 ng, or 100 ng). After reperfusion, the hearts were assessed for activation of the prosurvival pathway, Akt. Results: Infusion of transforming growth factor-alpha did not confer any additional functional protection compared with the vehicle, but myocardial tissue analysis revealed significantly increased activation of the Akt pathway in both the 10-ng and 100-ng groups. Conclusion: Preischemic infusion of transforming growth factor-alpha does not improve myocardial functional recovery after ischemia/reperfusion injury. Whereas transforming growth factor-alpha treatment does affect actions at the molecular level, these actions do not translate into an observable functional effect. This lack of improvement may point to a relative unimportance of transforming growth factor-alpha in myocardial signaling compared with other epidermal growth factor ligands.