Chronic idiopathic thrombocytopenic purpura (CITP) is an autoimmune disorder characterized by the production of autoantibodies against specific platelet antigens and characterized by low platelet counts in peripheral blood over a period of at least 6 months. Corticosteroids have been generally used as first line therapy with serious side effects. Previously, we described the beneficial effect of high dose folic acid (HDFA), 5 to 20 mg PO daily), in the therapy of this disease. Presently, we report the treatment of two patients with severe thrombocytopenia with HDFA. A 46 year old splenectomized woman (P1) and a 32 year old non-splenectomized man (P2), who were moderately refractory to prednisone and prednisolone, had a previous history of undifferentiated connective tissue disease characterized by one episode of arthritis (P2 with a positive rheumatoid factor and morning stiffness). Both patients had normal serum folic acid and vitamin B12, and no signs of megaloblastic or dysplastic alterations were evidenced in bone marrow aspirates. Ham test was negative and CD55/CD59 values for both patients were equal to normal controls. Bone marrow biopsies were also performed prior to the treatment with folic acid (FA) to evidence a global decrease in bone marrow cellularity (30% in case 1 and 20% in case 2). Concomitant infections or other diseases were excluded. Prednisone was tapered slowly, and high dose folic acid administration was initiated at this time. P1 achieved complete remission (CR) in 5 months with slowly tapering of folic acid during one year, remaining with normal platelet counts after one more year with no treatment. P2 achieved sustained partial remission (PR) with platelet counts ranging 63 x 109L to 113 x109/L. Interestingly, sequential bone marrow biopsies performed 2 years after the beginning of HDFA therapy revealed a marrow cellularity of 50% and 35% for P1 and P2, respectively. We demonstrated that the successful CR and PR to HDFA are associated with a significant increase in the overall bone marrow cellularity in both cases (20% in P1 and 15% in P2). Apoptotic features in idiopathic thrombocytopenic purpura (ITP) were characterized by Houwerzijl et al who demonstrated apoptosis and para-apoptosis as ultrastructural alterations in bone marrow megacaryocytes, supportive of ineffective thrombopoiesis as an underlying phenomenon in this study. Buemi et al demonstrated that addition of folic acid to the medium of vascular smooth muscle cells in culture inhibited the percentage of apoptotic and necrotic cells through a decrease in homocysteine concentration. The exact mechanism through which high dose folic acid is able to increase platelets measured in peripheral blood of patients with ITP and induce sustained CR and PR is so far unknown and remains to be explained. However, the present response to HDFA suggest a qualitative and especially quantitative role for this drug in protecting and upgrading the hematopoietic bone marrow and, consequently, restoring the platelet production in these 2 patients.