Objective: To evaluate the efficacy of HBOC-201 for resuscitation of hemorrhagic shock in a swine model incorporating soft tissue injury and delayed evacuation. Methods: A muscle crush injury and 40% estimated blood volume controlled hemorrhage was completed in 24 Yucatan mini-pigs. Pigs were untreated or resuscitated with HBOC-201 or 6% hetastarch (HEX) at 20 min. Invasive hemodynamics and clinical variables were monitored for 4 h (pre-hospital phase) and subsequent fluid infusions were administered for severe hypotension or tachycardia. Animals were recovered from anesthesia and monitored non-invasively to 72 h (hospital phase). Results: 100% (8/8) of HBOC-201-, 88% (7/8) of HEX-, and 63% (5/8) of non-resuscitated pigs, survived to 72 h (p = 0.27). Mean arterial pressure, mean pulmonary arterial pressure and systemic vascular resistance index were higher in HBOC-201 pigs. By 90 min, cardiac index was restored to baseline in the HBOC-201 group and was 1.4-fold greater than baseline in the HEX group. HBOC-201 pigs had lower fluid requirements than HEX pigs (18.8 ± 1.8 and 29.9 ± 1.1 ml/kg, p < 0.001) in the pre-hospital phase and required fewer blood transfusions (1.3 ± 1.3 and 9.4 ± 0.6 ml/kg, respectively, p < 0.001) in the hospital phase. Urine output and blood creatinine were comparable in HBOC-201 and HEX pigs. Tissue oxygenation levels were highest in the HBOC-201 group. Conclusions: As HBOC-201 restored hemodynamics and tissue oxygenation and decreased fluid requirements, in comparison with HEX, HBOC-201 was at least as efficacious and possibly a superior resuscitative fluid in a military-relevant delayed evacuation hemorrhagic shock swine model.