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There is limited clinical experience with the use of coagulation concentrates to reverse the effect of direct oral anticoagulants. We assess the achievement of effective clinical hemostasis with the use of 4-factor prothrombin complex concentrate (PCC) in patients on apixaban or rivaroxaban presenting with major bleeding. A retrospective chart review was conducted at a tertiary referral medical center in the USA. We assess the achievement of clinical hemostasis using 4-factor PCC in patients on chronic apixaban or rivaroxaban therapy presenting with major bleeding. Clinical hemostasis was assessed by the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. A total of 29 patients are included in the study. The most common site of bleeding was intracranial hemorrhage (ICH) (72.4%), followed by gastrointestinal bleed (13.8%). Clinical hemostasis was achieved in 21 (72.4%) patients. Patients who did not achieve clinical hemostasis (27.6%) suffered from ICH, and all of them died during hospitalization except for two patients who were discharged with neurologic deterioration. One patient developed multiple brain infarctions after receiving 4-factor PCC. Sixteen patients (55.2%) were receiving concomitant medications that interact with apixaban and rivaroxaban and increase the risk of bleeding. Four-factor PCC appears to be effective in achieving clinical hemostasis in patients on apixaban or rivaroxaban presenting with major bleeding. It may be an alternative to patients who need anticoagulation reversal if the specific antidote, andexanet alfa, is not available.