Thrombotic thrombocytopenic purpura (TTP) usually responds to daily single total plasma exchange (TPE) or to plasma infusion. However, some cases are refractory to total plasma exchange, and additional efficacious treatment may not be available. A 34-year-old white male diagnosed with TTP was found to be refractory to single TPE. Steroids and twice daily TPE, in addition to splenectomy and vincristine, worked well to prevent further clinical deterioration. Laboratory values were normalized at the completion of treatment protocol. Cases of TTP refractory to single TPE/day may benefit from early treatment of twice-daily TPE in addition to a combination therapy of steroids, splenectomy, and vincristine.