Polycythemia rubra vera is a chronic myeloproliferative disorder characterized by panmyelosis with the resultant potential for thrombosis, myelofibrosis, and acute leukemia. Treatment has rested on phlebotomy and hydroxyurea. In 2002, we reported two patients who were unable to tolerate hydroxyurea but responded to imatinib mesylate (Gleevec). These patients have remained in complete hematologic remission on imatinib since 1999. As a result we began a phase II, open label trial of imatinib in patients with polycythemia vera. Patients meeting the Polycythemia Vera Study group criteria for the diagnosis of polycythemia vera, either naïve or intolerant to prior treatment were allowed to enroll. Initial therapy was begun with imatinib mesylate at 400 mg a day and two dose escalations, one to 600 and second to 800 mg a day, were allowed for patients not achieving a target hematocrit of 44 or less; or a platelet count of less than 600,000/mm³. Twenty patients were enrolled, 15 achieved complete hematologic remission within 12 weeks and ten remain on study. Six patients remain in remission on 400 mg a day and four on 500 mg a day. Gastrointestinal or cutaneous toxicities were primarily grade I or II. All patients were negative for bcr/abl. Imatinib mesylate is capable of producing hematologic remission in the majority of patients with polycythemia vera and provides another option for patient management, particularly in those intolerant to hydroxyurea.