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Background: Currently, the standard of care for treating severe hemorrhage in a military setting is Combat Gauze (CG). Previous work has shown that hydrophobically modified chitosan (hm-C) has significant hemostatic capability relative to its native chitosan counterpart. This work aims to evaluate gauze coated in hm-C relative to CG as well as ChitoGauze (ChG) in a lethal in vivo hemorrhage model., Methods: Twelve Yorkshire swine were randomized to receive either hm-C gauze (n = 4), ChG (n = 4), or CG (n = 4). A standard hemorrhage model was used in which animals underwent a splenectomy before a 6-mm punch arterial puncture of the femoral artery. Thirty seconds of free bleeding was allowed before dressings were applied and compressed for 3 min. Baseline mean arterial pressure was preserved via fluid resuscitation. Experiments were conducted for 3 h after which any surviving animal was euthanized., Results: hm-C gauze was found to be at least equivalent to both CG and ChG in terms of overall survival (100% versus 75%), number of dressing used (6 versus 7), and duration of hemostasis (3 h versus 2.25 h). Total post-treatment blood loss was lower in the hm-C gauze treatment group (4.7 mL/kg) when compared to CG (13.4 mL/kg) and ChG (12.1 mL/kg) groups., Conclusions: hm-C gauze outperformed both CG and ChG in a lethal hemorrhage model but without statistical significance for key endpoints. Future comparison of hm-C gauze to CG and ChG will be performed on a hypothermic, coagulopathic model that should allow for outcome significance to be differentiated under small treatment groups., (Copyright © 2016 Elsevier Inc. All rights reserved.)