The mean time to death of mice infected with Venezuelan equine encephalomyelitis (VEE) virus was increased 2 days by antithymocyte serum (ATS) treatment given 1 day before and 1 day after virus inoculation. Virus assays of blood, brain, and spleen indicated that VEE virus replication was delayed by ATS. Additionally, mice treated with ATS exhibited neurological signs later than untreated mice. During the infection, the percentage of splenic B lymphocytes as determined by surface immunoglobulin staining increased. ATS treatment caused a further elevation of the percentage of splenic B lymphocytes. These results show a selective depletion of the non-immunoglobulin-bearing lymphocyte population during VEE virus infection and support the hypothesis that ATS destroys or alters an important population of cells associated with the normal course of pathogenesis and the replication of VEE virus to high titers in the mouse.