Little is known about the microvascular effects of blood replacement solutions. This study was undertaken to develop an animal model suitable for studies of the microcirculatory effects of such solutions and to investigate microvascular responses to isovolemic transfusion with stroma-free hemoglobin (SFH), whole donor blood, or a new potential blood substitute solution containing oxypolyhemoglobin (OPH) as an oxygen carrier. Hamster livers were exposed and the microcirculation studied using intravital epifluorescent video microscopy. 33% blood volume replacement with SFH elevated systemic blood pressure by 25 Torr. Accompanying this increase in pressure was a 36% decrease in sinusoidal blood flow velocity and a 10% decrease in terminal hepatic venular diameters. Terminal portal venular diameters did not change. Decrease in liver sinusoidal perfusion was not due to neutrophil mediated injury, as myeloperoxidase activity in jejunum, liver, kidney, and lung remained unchanged. The reduction in perfusion was likely due to systemic vasoconstriction produced by SFH. In contrast, transfusion with whole blood did not change any of the measured parameters showing the excellent stability of the model. OPH transfused animals exhibited only a small 10 Torr transient increase in MAP 15 min post-transfusion. By 30 min MAP returned to the pre-infusion value. No significant changes were observed in either venular diameters or sinusoidal velocities in this group of animals. These results demonstrate suitability of this model for studies of the microcirculatory and hemodynamic effects of blood replacement solutions. Furthermore, OPH solution produced only minor transient disturbances in microvascular and systemic parameters.