Background: Death from uncontrolled hemorrhage occurs rapidly, particularly among combat casualties. The US military has used warm fresh whole blood during combat operations owing to clinical and operational exigencies, but published outcomes data are limited. We compared early mortality between casualties who received warm fresh whole blood versus no warm fresh whole blood. Methods: Casualties injured in Afghanistan from 2008 to 2014 who received ≥2 red blood cell containing units were reviewed using records from the Joint Trauma System Role 2 Database. The primary outcome was 6-hour mortality. Patients who received red blood cells solely from component therapy were categorized as the non–warm fresh whole blood group. Non– warm fresh whole blood patients were frequency-matched to warm fresh whole blood patients on identical strata by injury type, patient affiliation, tourniquet use, prehospital transfusion, and average hourly unit red blood cell transfusion rates, creating clinically unique strata. Multilevel mixed effects logistic regression adjusted for the matching, immortal time bias, and other covariates. Results: The 1,105 study patients (221 warm fresh whole blood, 884 non–warm fresh whole blood) were classified into 29 unique clinical strata. The adjusted odds ratio of 6-hour mortality was 0.27 (95% confidence interval 0.13–0.58) for the warm fresh whole blood versus non–warm fresh whole blood group. The reduction in mortality increased in magnitude (odds ratio = 0.15, P =.024) among the subgroup of 422 patients with complete data allowing adjustment for seven additional covariates. There was a dose-dependent effect of warm fresh whole blood, with patients receiving higher warm fresh whole blood dose (>33% of red blood cell–containing units) having significantly lower mortality versus the non–warm fresh whole blood group. Conclusion: Warm fresh whole blood resuscitation was associated with a significant reduction in 6-hour mortality versus non–warm fresh whole blood in combat casualties, with a dose-dependent effect. These findings support warm fresh whole blood use for hemorrhage control as well as expanded study in military and civilian trauma settings.