Rabbits and rats are becoming popular models for in vitro as well as in situ studies of myocardial infarction. In the present analysis we evaluated the results of several of our completed investigations and tested whether blood-free perfusate, anesthesia, or risk zone size affects infarction in these species. In addition, the influence of the method used for determining infarct size (histology or histochemistry) was examined in rabbits. All hearts experienced 30 min of regional ischemia followed by either 2-3 h of reperfusion in animals in which infarct size was assessed by staining with triphenyltetrazolium chloride or 72 h in those in which histological methods were used to measure infarct size. Eighteen rabbit and seven rat hearts perfused with Krebs buffer, seventeen open-chest rabbits, eight rats anesthetized with pentobarbital, and ten conscious rabbits were studied. Risk zone size measured with fluorescent particles was plotted against infarct size. Infarct size was linearly correlated with risk zone size and did not differ among models for each species. In rat hearts the regression line passed through the origin so that zero infarction occurred with zero risk zone size. However, in the rabbit heart there was no apparent infarction for risk zone sizes < 0.3 cm3. Although the relationship between risk zone and infarction was found to be remarkably independent of the model chosen, the nonzero intercept for the rabbit heart can be an important, previously unrecognized source of experimental variability when infarct size is expressed as a percentage of the risk zone.