We investigated the efficacy of interferon-alpha (IFN-alpha) treatment in 5 patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). Treatment with IFN-alpha yielded clinical improvement of gait, and sensory and/or sphincter disturbance in 4 out of the 5 HAM patients. IFN-alpha treatment did not bring about uniform changes in lymphocyte subsets or anti-HTLV-I antibody titer of peripheral blood. Although the stimulation indexes to phytohemagglutinin, concanavalin A, and pokeweed mitogen were decreased in the culture of the peripheral blood lymphocytes (PBL) in the 5 HAM patients before the treatment, the stimulation indexes to these mitogens were significantly increased except in 1 case after the IFN-alpha treatment. These changes were based primarily on the depression of the spontaneous proliferation of PBL without mitogen. These results appear to point out a very important phenomenon for the investigation of the pathogenesis of HAM.