Objectives: To test our hypothesis that the hemoglobin based oxygen carrier HBOC-201 would have similar or superior efficacy to 6% hetastarch (HEX) as a pre-hospital 'bridging' fluid for hemorrhagic shock when delay to definitive medical care is prolonged to 24 h. Methods: Twenty-four pigs were anesthetized, instrumented, given a soft tissue injury, and bled 55% estimated blood volume. Pigs were randomized to receive HBOC-201, HEX, or no resuscitation fluids (NON). At 4 h post-injury, surgical sites were repaired and pigs were recovered from anesthesia. Animals were non-invasively monitored, administered blood for anemia or saline for hypotension at 24 and 48 h, and monitored for 72 h. Results: Survival to 72 h was 87.5% (7/8) in HBOC-201 and HEX pigs compared to 25% (2/8) in NON pigs (p = 0.01). Increased mean arterial pressure was observed in the HBOC-201 group (p < 0.0001). Cardiac index was highest in HEX pigs (overall p < 0.001, HBOC-201 versus HEX p = 0.002). Transcutaneous tissue oxygenation was higher with HBOC-201 (overall p = 0.04, HBOC-201 versus HEX p < 0.01). HBOC-201 and HEX pigs had comparable heart rates, pulmonary pressures, pre-hospital fluid requirements, venous O2 saturation, base deficit, and lactic acid. Hemoglobin was decreased with HEX (overall p < 0.0001, HBOC-201 versus HEX p < 0.0002). At 24 h, 14.3% (1/7) HBOC-201 pigs required blood transfusions versus 100% HEX (7/7) and NON (2/2) pigs (p > 0.001). Conclusions: HBOC-201 restored hemodynamics, maintained tissue oxygenation, and decreased blood transfusions in comparison to HEX in severe controlled HS with 24 h delay to simulated hospital care. These results support the potential use of HBOC-201 as a bridging resuscitation fluid for HS. © 2007.