BACKGROUND: Factor (F)XIII deficiency is a rare inherited bleeding disorder, but can also be acquired due to the development of inhibitors. CASE REPORT: A 17-year-old female with systemic lupus erythematosus and end-stage kidney disease secondary to Class IV lupus nephritis developed spontaneous subcutaneous and muscular hematomas and delayed major bleeding after invasive procedures. She had abnormal kaolin thromboelastography (kTEG; decreased maximal amplitude, representative of clot strength) initially attributed to thrombocytopenia and uremic platelet dysfunction, but her FXIII activity was undetectable, and a high-titer antibody against FXIII was identified. She had improvement in clinical bleeding and in kaolin thromboelastogram result and transient improvement in FXIII activity after each dose of plasma-derived FXIII concentrate (Corifact) or cryoprecipitate. Her inhibitor titers gradually improved with multiple immunosuppressive therapies and plasma exchange. While her FXIII activity level remained mildly decreased, she has not had additional significant bleeding. CONCLUSION: Treatment with either plasma-derived FXIII or cryoprecipitate is an effective treatment to normalize the kTEG variables and clinical bleeding diatheses associated with acquired FXIII inhibitors. Higher doses may be needed in patients with high-titer inhibitor.