Two chronic animal models and one acute animal model were used to evaluate exchange transfusion with stroma-free hemoglobin solutions. A direct comparison was made between stroma-free hemoglobin solutions having differing oxygen offloading characteristics as well as a colloid solution consisting of 7% bovine albumin. These studies involved a partial exchange involving approximately 50% of the animal's blood volume to simulate a clinically more appropriate partial blood replacement situation. We noted a consistent increase in the arterial oxygen content of animals exchanged with the stroma-free hemoglobin solutions and some modest improvement in oxygen dynamics. Our studies examining myocardial contractility, especially those carried out in the right heart bypass swine preparation failed to substantiate any difference between an exchange with albumin or stroma-free hemoglobin solutions. The conscious animal models examined both at rest and at exercise demonstrated marked differences in exercise response. Animals exchanged transfused with stroma-free hemoglobin solutions often had an almost normal exercise response while those animals exchanged with non-oxygen carrying albumin solution frequently failed to exercise on a treadmill. Blood flow measurements using radiolabeled microspheres were performed in chronically instrumented swine. These animals had a normal variation in organ blood flow during exercise which was noted both during the control period as well as following exchange with stroma-free hemoglobin solutions. Animals exchanged transfused with albumin had a marked derangement in organ blood flow apparently reflecting the decreased oxygen availability. Results from these three studies substantiate a significant benefit to animals undergoing a 50% exchange when that exchange is done with an oxygen carrying solution such as stroma-free hemoglobin solutions as opposed to a non-oxygen carrying but oncotically active solution such as albumin solution. These studies seem to offer encouragement to the continued investigation and ultimate clinical utilization of hemoglobin solutions as an appropriate blood substitute.