In an attempt to characterize the immunologic reactivity of cerebrospinal-fluid lymphocytes in demyelinating diseases, we compared the myelin-basic-protein-induced in vitro responses of these cells to peripheral blood lymphocytes from the same subjects with a variety of neurologic diseases. Peripheral blood lymphocytes from patients with acute disseminated encephalomyelitis and progressive multiple sclerosis had increased reactivity as compared to those of normal volunteers (P less than 0.01 and P less than 0.05, respectively). Cerebrospinal-fluid lymphocytes from patients with acute disseminated encephalomyelitis and acute and progressive (but not stable) multiple sclerosis were more reactive than cells from subjects with other neurologic diseases (P less than 0.005, P less than 0.02 and P less than 0.05, respectively). Cerebrospinal-fluid lymphocytes manifested a greater reactivity than peripheral blood lymphocytes in acute and progressive multiple sclerosis but not in acute disseminated encephalomyelitis. These findings demonstrate that lymphocytic cells reactive to myelin basic protein are present in the spinal fluid during active demyelinating disease; and that these cells may be more reactive than peripheral blood lymphocytes.