Although lymphocyte turnover in chronic human immunodeficiency virus and simian immunodeficiency virus (SIV) infection has been extensively studied, there is little information on turnover in acute infection. We carried out a prospective kinetic analysis of lymphocyte proliferation in 13 rhesus macaques inoculated with pathogenic SIV. A short-lived dramatic increase in circulating Ki-67⁺lymphocytes observed at 1 to 4 weeks was temporally related to the onset of SIV replication. A 5- to 10-fold increase in Ki-67⁺ CD8⁺ T lymphocytes and a 2- to 3-fold increase in Ki-67⁺ CD3⁻ CD8⁺natural killer cells accounted for >85% of proliferating lymphocytes at peak proliferation. In contrast, there was little change in the percentage of Ki-67⁺ CD4⁺ T lymphocytes during acute infection, although transient increases in Ki-67⁻and Ki-67⁺ CD4⁺ T lymphocytes expressing CD69, Fas, and HLA-DR were observed. A two- to fourfold decline in CD4⁺ T lymphocytes expressing CD25 and CD69 was seen later in SIV infection. The majority of Ki-67⁺ CD8⁺ T lymphocytes were phenotypically CD45RA⁻CD49d^hi Fas^hi CD25⁻CD69⁻ CD28⁻ HLA-DR⁻ and persisted at levels twofold above baseline 6 months after SIV infection. Increased CD8⁺ T-lymphocyte proliferation was associated with cell expansion, paralleled the onset of SIV-specific cytotoxic T-lymphocyte activity, and had an oligoclonal component. Thus, divergent patterns of proliferation and activation are exhibited by CD4⁺ and CD8⁺ T lymphocytes in early SIV infection and may determine how these cells are differentially affected in AIDS.