The lesions of visna may represent an immunopathologic process. To test this hypothesis, a 1 mo. schedule of immunosuppressive treatment was devised, using horse antisheep thymocyte serum. In Hampshire sheep, this regime protected against experimental allergic encephalomyelitis, inhibited development of tuberculin hypersensitivity, retarded rejection of skin homografts by 3 wk and markedly reduced the number and mitogenic responsiveness of peripheral blood lymphocytes. Two groups of Icelandic sheep received intracerebral inoculations of visna virus, and 1 group was treated with horse antisheep thymocyte serum supplemented by a short terminal course of cyclophosphamide. CNS lesions were seen in only 1 of 8 suppressed animals at sacrifice 25 days after infection; definite lesions were present in 8 of 8 infected control animals. The frequency of CNS virus isolation was similar in the 2 groups, indicating that treatment suppressed the cellular proliferative response without preventing the CNS phase of infection. Sheep receiving horse antisheep thymocyte serum had a reduced number of virus isolations from peripheral lymphoid tissue, presumably reflecting the lympholytic effect of treatment. These observations are consistent with the immunopathologic hypothesis and suggest several different ways in which suppression could modify the immune response to visna virus.