Thrombotic thrombocytopenic purpura (TTP) is a microangiopatic thrombotic state associated with a deficiency on the cleavage function of the Von Willebrand factor polymers by a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13. We report a patient with relapsing TTP successfully treated with N-acetylcysteine (NAC) after failure of plasma exchange (PE) with steroids, rituximab, cyclophosphamide, vincristine, and azathioprine. A 51-year-old male who had an altered mental status while he was on rehabilitation for a previously treated TTP with a subsequent neurologic deficit. He was treated 7 days ago with PE plus steroids and subsequently discharged to our facility for rehabilitation. He was found to have a platelet level of 153,000/mm, hemoglobin decreased from 9.2 to 6.2 g/dL, creatinine raised from 1.0 to 2.4 mg/dL, and the peripheral smear showed schistocytes. A brain computed tomography showed a subacute infarction in the left frontal lobe and an abdominal-pelvic computed tomography disclosed a retroperitoneal hematoma. PE and steroids were started for 14 days. On day 15th, rituximab was added weekly for 10 cycles. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 activity level was 95% without platelet count improvement. We started cyclophosphamide, then vincristine, and finally azathioprine. His platelet were maintained above 150,000/mm for a few days. He had several episodes of sepsis after every chemotherapeutic drug. On day 135th, NAC was commenced at 150 mg/kg for 10 days along with PE and low-dose steroids for 10 days. Complete recover of platelet count was achieved and the patient was successfully discharged. Relapsing TTP is often difficult to manage and may last longer than expected carrying several comorbidities and complications. PE plus steroids are the mainstay of TTP treatment and Rituximab is the drug of choice after they have failed. The patient had a complete remission after NAC therapy. Hence, NAC likely can be considered an earlier choice of treatment after rituximab, before the use of chemotherapeutic agents, considering its toxic and adverse effects.