Human T cell leukemia virus type 1 (HTLV-1) infects both CD4⁺ and CD8⁺ lymphocytes, yet it induces adult T cell leukemia/lymphoma (ATLL) that is regularly of the CD4⁺ phenotype. Here we show that in vivo infected CD4⁺ and CD8⁺ T cells displayed similar patterns of clonal expansion in carriers without malignancy. Cloned infected cells from individuals without malignancy had a dramatic increase in spontaneous proliferation, which predominated in CD8⁺ lymphocytes and depended on the amount of tax mRNA. In fact, the clonal expansion of HTLV-1–positive CD8⁺ and CD4⁺ lymphocytes relied on 2 distinct mechanisms — infection prevented cell death in the former while recruiting the latter into the cell cycle. Cell cycling, but not apoptosis, depended on the level of viral-encoded tax expression. Infected tax-expressing CD4⁺ lymphocytes accumulated cellular defects characteristic of genetic instability. Therefore, HTLV-1 infection establishes a preleukemic phenotype that is restricted to CD4⁺ infected clones.