To avoid the compensatory hemodynamic responses, which have limited interpretation of hemoglobin-oxygen affinity modifications in animal experimentation, an isolated blood-perfused rabbit heart model providing metabolic, functional, and vectorcardiographic measurements has been developed. Fixed-flow perfusions of unchanged or affinity-modified red blood cell suspensions were carried out to assess the benefits of high affinity during hypoxic hypoxia and of low affinity during posthypoxic recovery. Using fully saturated suspensions, the influence of affinity level during restricted flow and reperfusion was also studied. Higher myocardial oxygen consumption (MVO2) was associated with high-affinity blood during mild hypoxia and low-affinity blood during posthypoxic recovery. At low flows, heart rate and MVO2 tended to be lower in high-affinity perfusions, and to recover more completely during low-affinity reperfusions. Ventricular function, vectorcardiographic patterns, and lactate levels were affected by hypoxia and ischemia, but not by level of affinity. The relevance of these observations to the therapeutic potential of hemoglobin-oxygen affinity modification is discussed.