Idiopathic thrombocylopenia purpura (ITP) is an autoimmune disorder characterized by thrombocytopenia with a normal bone marrow and no other causes of thrombocylopenia. Initial therapy consists of corticosteroids, often with IVIG. Most adults have chronic disease and require splenectomy. Together, steroids and splenectomy induce responses in 75% of patients. Patients that have unsafe levels of platelets despite treatment or who require high doses of steroids may require alternate forms of therapy such as vinca alkaloids, danazol, immunosuppressive medications and chemotherapy. Unfortunately, responses to second line therapies are uncommon and some patients are refractory to all forms of therapy. We report on 12 patients with chronic refractory ITP treated with combination chemotherapy consisting of cyclophosphamide and cyclosporine. All patients seen in a hematology clinic specializing in the treatment of ITP from 07/98 to 07/00 were reviewed. In 618 charts, 12 patients were identified who had been treated with concurrent cyclophosphamide and cyclosporine. Five patients were female, 7 were male. The average age was 50 yrs (range 21-74). All patients had severely refractory disease and had failed previous medications including corticosteroids,IVIG, anti-D, vincristine, azathioprine. methotrexate, leflunomide and mycophenolate. Eight patients (75%) had been treated with cyclophosphamide without response. All patients had undergone a splenectomy. At initiation of therapy, the mean platelet count was 10 xlO'/L (range 1-39). Patients were treated with cyclophosphamide 100 mg daily and cyclosporine 50-100 mg daily. Mean duration of follow-up was 54.5 weeks (range 10-104). Clinical response to therapy was defined as a complete response (CR) (platelets150 xlO'/L), partial response (PR)(platelets50 xlO'/L) or no response (platelets<50 xlO'/L). A CR was seen in 3 patients (25%). A PR was seen in 2 patients (16.7%) giving an overall response rate of 42%. Seven patients (58.3%) failed to respond. The mean time to response was 31.8 weeks (range 13-49). Of the 5 patients who achieved a CR or PR, 3 patients remain in CR or PR. The treatment was well tolerated in most patients. Cyclophosphamide was discontinued in 2 patients because of nausea and GI distress and in 1 patient because of leukopenia. Combination chemotherapy consisting of cyclophosphamide and cyclosporine can help patients with very severe chronic ITP who are refractory to other medications and splenectomy.