Early viral replication and profound CD4⁺ T-cell depletion occur preferentially in intestinal tissues of macaques infected with simian immunodeficiency virus (SIV). Here we show that a much higher percentage of CD4⁺ T cells in the intestine express CCR5 compared with those found in the peripheral blood, spleen, or lymph nodes. In addition, the selectivity and extent of the CD4⁺ T-cell loss in SIV infection may depend upon these cells coexpressing CCR5 and having a “memory” phenotype (CD45RA⁻). Following intravenous infection with SIVmac251, memory CD4⁺ CCR5⁺ T cells were selectively eliminated within 14 days in all major lymphoid tissues (intestine, spleen, and lymph nodes). However, the effect on CD4⁺T-cell numbers was most profound in the intestine, where cells of this phenotype predominate. The CD4⁺ T cells that remain after 14 days of infection lacked CCR5 and/or were naive (CD45RA⁺). Furthermore, when animals in the terminal stages of SIV infection (with AIDS) were examined, virtually no CCR5-expressing CD4⁺ T cells were found in lymphoid tissues, and all of the remaining CD4⁺ T cells were naive and coexpressed CXCR4. These findings suggest that chemokine receptor usage determines which cells are targeted for SIV infection and elimination in vivo.