Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4⁺ T cells, a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound and selective depletion of CD4⁺ T cells in the intestine within days of infection, before any such changes in peripheral lymphoid tissues. The loss of CD4⁺ T cells in the intestine occurred coincident with productive infection of large numbers of mononuclear cells at this site. The intestine appears to be a major target for SIV replication and the major site of CD4⁺ T cell loss in early SIV infection.