We found unstimulated (spontaneous) peripheral blood lymphocyte (PBL) proliferation significantly increased in 14 patients with human T-lymphotropic virus (HTLV)-I-associated myelopathy (HAM) compared with findings in HTLV-I seropositive non-HAM carriers (N = 8) or HTLV-I seronegative controls (N = 16). The proliferative response to phytohemagglutinin, concanavalin A, or pokeweed mitogen was decreased in the HAM patients. Cell clusters were frequent in cultures of unstimulated PBL from the HAM patients, but much less common in the controls or carriers. This spontaneous PBL proliferation was depressed when adherent-cell populations were depleted from the cultures. IL-2 activity increased in the supernatant of 3-day cultured cells from HAM patients, but not in cultured cells from the controls. Since IL-2 receptor positive cells increased in HAM, this spontaneous PBL proliferation is probably a response to IL-2 through the expression of IL-2 receptors.