The aim of this study was to determine the effect of different administration protocols on the cardioprotective efficacy of the non-selective, irreversible caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) and bocaspartyl-(OMe)-fluoromethylketone (BocD.fmk) in a rat in vivo ischemia and reperfusion paradigm. Hearts were made ischemic for 45 min and reperfused for 180 min. Under these conditions, it was determined that zVAD.fmk was cardioprotective when administered before or after the onset of ischemia, whereas BocD.fmk was efficacious only when administered before the onset of ischemia. This is the first report of in vivo cardioprotection by a caspase inhibitor when administered after the onset of ischemia.