Background and Aim: Despite great efforts during the last decades, acute myocardial infarction (MI) contributes to significant mortality statistics with growing yearly prevalence. The cardioprotective effect of the phosphodiesterase5-inhibitor, Sildenafil (Sil) against MI and its complications stills a matter of debate and controversy. So, we aimed to investigate the impact of Sil pretreatment on the outcome of isoprenaline (ISO)-induced infarct-like lesions and comparing it to that of vitamin E (Vit.E). Methods: 5 groups of rats were conducted; Control and ISO-injected group (75mg/kg; i.p) to induce infarct-like lesion in addition to 3 groups that were pretreated with either oral Sil (10mg/kg/day) and/or oral Vit.E (100IU/kg/day) for 3 weeks before injection of ISO. Results: the preconditioning with Sil or Vit.E significantly ameliorated ECG alterations, decreased serum levels of the cardiac enzyme CK-MB, and reduced cardiac injury score with no evident necrotic changes on histopathological examination that were observed in the ISO-induced MI. These changes were accompanied by significant increases in the cardiac SOD content and decreases in MDA content in addition to reduced immunohistochemical expression of transforming growth factor β (TGFβ) that plays an outstanding role in post-infarct remodeling. Conclusion: Sil and/or Vit.E exerted a prophylactic effect against MI and post-infarct remodeling, at least in part, through preserving the cardiac redox balance and antifibrotic effect by lowering TGFβ.