To evaluate the efficacy of international normalized ratio (INR) reversal using four-factor prothrombin complex concentrate (4F-PCC) in nonmedication-induced coagulopathy. We performed a single-site, retrospective cohort study of patients receiving off-label use of 4F-PCC. Cohorts included liver dysfunction if they had acute liver decompensation or cirrhosis without other causative factors of liver failure such as sepsis, coagulopathy of acute sepsis (CAS) if they had documentation of sepsis and no underlying liver disorder, known factor deficiencies, or medication-induced coagulopathy, or warfarin if they were taking warfarin. Patients with unknown medication or direct oral anticoagulant usage were excluded. 4F-PCC was administered 32 times in 26 patients for nonvitamin-K antagonist related coagulopathy (11 CAS and 21 liver dysfunction) and 47 administrations were in warfarin patients. Liver dysfunction patients had a mean model for end-stage liver disease score of 28 ± 10. CAS and warfarin patients had significant INR reductions (ΔINR 1.9, P < 0.01; ΔINR 3.9, P < 0.01, respectively). Liver dysfunction patients mean change in INR trended toward significance (ΔINR 0.7, P = 0.09). Patients who received 4F-PCC based upon previously established dosing guidelines for moderate elevations in INR (20–30 IU/kg) doing demonstrated similar reductions in INR between CAS and warfarin patients (ΔINR 1.3, P = 0.03, ΔINR 1.0 P < 0.01, respectively). 4F-PCC significantly reduces the INR in CAS patients and trended toward significant reductions in liver dysfunction patients. Adequately powered, prospective trials are needed to demonstrate 4F-PCC efficacy in reversal of these coagulopathies.