Numerous drugs were tested for ability to suppress the hyperacute form of experimental allergic encephalomyelitis (EAE). This very severe disease produced clinical signs after 7-9 days which progressed rapidly to paralysis and death. Treatment during the first five days of the incubation period with cycloleucine, cyclophosphamide EN3638, 6-mercaptopurine, methotrexate and procarbazine produced important delays in onset. Corticosteroids, nonsteroidal antiinflammatory drugs, antilymphocyte serum, asparaginase, gold, cytarabine and tilorone, all previously reported to suppress ordinary EAE, had moderate, little or no effect in hyperacute EAE. Proteacted treatment was of no avail with some of these drugs, but it revealed the remarkable suppressive effect of EN3638, equal to cyclophosphamide. Hyperacute EAE was a rapid and economical screening test for immunosuppressive drugs, and a highly discriminating tool for comparison of potent agents.