Hemoglobin vesicles (HbVs) are artificial oxygen (O2) carriers that encapsulate concentrated hemoglobin (Hb) solution in phospholipid vesicles (liposomes). Recent reports on cytoprotective effects of exogenous carbon monoxide (CO) urged us to test infusion of CO-bound HbV (CO-HbV) and red blood cells (CO-RBC) in hemorrhagic-shocked rats to improve tissue viability over that of O2-bound HbV (O2-HbV) and O2-bound RBC (O2-RBC). Male Wistar rats were anesthetized with 1.5% sevoflurane inhalation (FiO2 = 21%) while spontaneous breathing was maintained. Shock was induced by 50% blood withdrawal from femoral artery. Fifteen minutes later, they received CO-HbV, CO-RBC, O2-HbV, O2-RBC, or empty vesicles (EV) suspended in 5% recombinant albumin. All groups showed prompt recovery of blood pressure and blood gas parameters just after resuscitation and survived for 6 h of observation period. However, only the EV group showed significant hypotension at 3 and 6 h. Plasma enzyme levels were elevated at 6 h, especially in the O2-HbV, O2-RBC, and EV groups. They were significantly lower in the CO-HbV and CO-RBC groups than in the O2-bound fluids. Immunohistochemical staining of 3-nitrotyrosine exhibited less oxidative damage in the liver and lung for CO-HbV and CO-RBC groups. Blood carbonyl Hb levels (26%-39% immediately after infusion) decreased to less than 3% at 6 h while CO was exhaled through the lung. Both HbV and RBC gradually gained the O2 transport function. Collectively, both CO-HbV and CO-RBC showed a resuscitative effect for hemorrhagic-shocked rats. They reduced oxidative damage to organs in comparison to O2-HbV and O2-RBC. Adverse and poisonous effects of CO gas were not evident for 6 h in this experimental model. Further study is necessary to clarify the neurological impact of a longer observation period for eventual clinical applications.