A phospholipid vesicle encapsulating hemoglobin (Hb vesicle, HbV) has been developed to provide O₂-carrying capacity to plasma expanders. Its ability to restore systemic and microcirculatory conditions after hemorrhagic shock was evaluated in the dorsal skinfold window preparation of conscious hamsters. The HbV was suspended in 8% human serum albumin (HSA) at Hb concentrations of 3.8 g/dl [HbV(3.8)/HSA] and 7.6 g/dl [HbV(7.6)/HSA]. Shock was induced by 50% blood withdrawal, and mean arterial pressure (MAP) at 40 mmHg was maintained for 1 h by the additional blood withdrawal. The hamsters receiving either HbV(3.8)/HSA or HbV(7.6)/HSA suspensions restored MAP to 93 ± 14 and 93 ± 10 mmHg, respectively, similar with those receiving the shed blood (98 ± 13 mmHg), which were significantly higher by comparison with resuscitation with HSA alone (62 ± 12 mmHg). Only the HSA group tended to maintain hyperventilation and negative base excess after the resuscitation. Subcutaneous microvascular blood flow reduced to ~10-20% of baseline during shock, and reinfusion of shed blood restored blood flow to ~60-80% of baseline, an effect primarily due to the sustained constriction of small arteries A₀ (diameter 143 ± 29 µm). The HbV(3.8)/HSA group had significantly better microvascular blood flow recovery and nonsignificantly better tissue oxygenation than of the HSA group. The recovery of base excess and improved tissue oxygenation appears to be primarily due to the increased oxygen-carrying capacity of HbV fluid resuscitation.