Background: Blunt traumatic brain injury (bTBI) and uncontrolled hemorrhagic shock (UCHS) are common causes of mortality in polytrauma. We studied the influence of fresh frozen plasma (FFP) resuscitation in a rat model with both bTBI and UCHS before achieving hemorrhage control. Methods: The bTBI was induced by an external weight drop (200 g) onto the bare skull of anesthetized male Lewis (Lew/SdNHsd) rats; UCHS was induced by resection of two-thirds of the rats’ tails. Fifteen minutes following trauma, bTBI+UCHS rats underwent resuscitation with FFP or lactated Ringer’s solution (LR). Eight groups were evaluated: (1) Sham; (2) bTBI; (3) UCHS; (4) UCHS+FFP; (5) UCHS+LR; (6) bTBI+UCHS; (7) bTBI+UCHS+FFP; and (8) bTBI+UCHS+LR. Bleeding volume, hematocrit, lactate, mean arterial pressure (MAP), heart rate, and mortality were measured. Results: The study included 97 rats that survived the immediate trauma. Mean blood loss up to the start of resuscitation was similar among UCHS only and bTBI+UCHS rats (P=0.361). Following resuscitation, bleeding was more extensive in bTBI+UCHS+FFP rats (5.2 mL, 95% confidence interval [CI] 3.7, 6.6) than in bTBI+UCHS+LR rats (2.5 mL, 95% CI 1.2, 3.8) and bTBI+UCHS rats (1.9 mL, 95% CI -0.2, 3.9) (P=0.005). Similarly, non-significant increases in blood loss were observed in UCHS+FFP rats (P=0.254). Overall mortality increased if bleeding was above 4.5 mL (92.3% versus 8%; P<0.001). Mortality was 83.3% (10/12) in bTBI+UCHS+FFP rats, 41.7% (5/12) in bTBI+UCHS+LR rats, and 64.3% (9/14) in bTBI+UCHS rats. Conclusion: The bTBI did not exacerbate bleeding in rats undergoing UCHS. Compared to LR, FFP resuscitation was associated with a significantly increased blood loss in bTBI+UCHS rats.