Human polymerized hemoglobin (PolyHeme) is a universally compatible oxygen carrier developed for use when red blood cells are unavailable and oxygen-carrying replacement is needed to treat life-threatening anemia. This multicenter phase III trial assessed survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. Patients resuscitated with PolyHeme had outcomes comparable to those receiving the standard of care including rapid access to stored red blood cells. Although there were more adverse events in the PolyHeme group compared with control patients receiving blood, the observed safety profile is acceptable for the intended population. The benefit-to-risk ratio of PolyHeme is favorable when blood is needed but is not available or an option.