Introduction: Lyophilization may facilitate production of a safe, portable, easily storable, and transportable source of platelets for bleeding patients. The objective of this study was to examine the impact of lyophilized human and porcine platelets in a swine liver injury model of nonsurgical hemorrhage. Methods: Anesthetized pigs (40 kg) had a controlled 35% total blood volume bleed from the right jugular vein followed by cooling to 35°C and resuscitation with Ringer’s lactate to achieve a 3:1 blood withdrawal resuscitation. Through a midline laparotomy, the liver was injured with two standardized 5 × 5-cm grids with lacerations 1 cm apart and 0.5 cm deep. After 2 min of uncontrolled hemorrhage, the animals were treated with placebo (n = 5), lyophilized human (n = 5, HP), or swine platelets (n = 5, SP). At 15 min, shed blood was calculated. The animals then underwent abdominal closure. At 48 h, the animals were killed for histopathologic evaluation of the lung, kidney, and heart. Results: Intraoperative blood loss at 15 min was significantly higher in the HP arm (SP: 4.9 ± 2.9 mL/kg, HP: 12.3 ± 4.7 mL/kg, and control: 6.1 ± 2.5 mL/kg; P = 0.013). Mortality at 48 h was 20% in all three arms, due to uncontrolled intra-abdominal bleeding. At the time the animals were killed, SP animals had a significantly higher hematocrit (SP: 22.0% ± 3.0%, HP: 15.1% ± 4.9%, and control: 13.9% ± 0.6%; P = 0.026). No significant difference was found in platelet count (SP: 319.3 ± 62.1 × 103/µL, HP:361.5 ± 133.6 × 103/µL, and control: 242.7 ± 42.5 × 103/µL; P = 0.259). Histopathology of kidneys, lungs, and heart demonstrated no evidence of thromboembolic complications. Conclusion: In this swine model of liver injury, human lyophilized platelets increased intraoperative blood loss. With the use of species-specific lyophilized platelets, however, this effect was abolished, with a decrease in blood loss at 48 h after injury.