Rituximab is a monoclonal antibody directed against the CD20 antigen found on both malignant and normal B lymphocytes. It was given FDA approval in 1997 for relapsed or refractory, low grade or follicular, CD20+ non-Hodgkin’s lymphoma. We report the use of selective B-cell depletion with Rituximab on a fifty-nine year old male with acquired Factor VIII inhibitor who failed to respond to convential therapy. The patient presented with compartment syndrome of the left calf due to spontaneous severe hematoma, and was subsequently hospitalized. The patient was found to have a PTT of 86, Factor VIII <3%, and Factor VIII inhibitor 108 b.u. The patient had completed forty-eight weeks of interferon and ribavirin for Hepatitis C one month prior to admission. The PTT was normal nineteen months prior when liver biopsies were obtained. The patient was subsequently diagnosed with acquired Factor VIII deficiency, thought to be secondary to either the Hepatitis C infection or the interferon therapy. He improved with Factor VIII concentrate therapy, but did not spontaneously recover from the inhibitor. He had minimal response to IVIG. Rituxin was subsequently started (intravenously at 375mg/m2) once a week for eight consecutive weeks, and repeated every six months. After four cycles, a consistent response was documented by increased Factor VIII activity (as high as 62%), and decreased Factor VIII inhibitor (stable at <0.5%). The treatment was well tolerated, and no infusion related side effects were observed. The patient did well with no bleeding on maintenance therapy for approximately twenty-one months. Unfortunately, two weeks after completion of the fourth cycle the patient suffered a ruptured AAA, and upon surgical intervention became unresponsive and a right cerebral infarct was identified. The patient’s family subsequently discontinued life support and the patient died. This experience suggests that further investigation of Rituximab therapy in this defined population might benefit similar patients.