The HIV reservoir forming at the earliest stages of infection is likely composed of CCR5⁺ cells, because these cells are the targets of transmissible virus. Restriction of the CCR5⁺ reservoir, particularly in the gut, may be needed for subsequent cure attempts. Strategies for killing or depleting CCR5⁺ cells have been described, but none have been tested in vivo in nonhuman primates, and the extent of achievable depletion from tissues is not known. In this study we investigate the efficacy of two novel cytotoxic treatments for targeting and eliminating CCR5⁺ cells in young rhesus macaques. The first, an immunotoxin consisting of the endogenous CCR5 ligand RANTES fused with Pseudomonas exotoxin (RANTES-PE38), killed CCR5⁺ lamina propria lymphocytes (LPLs) ex vivo, but had no detectable effect on CCR5⁺ LPLs in vivo. The second, a primatized bispecific antibody for CCR5 and CD3, depleted all CCR5⁺ cells from blood and the vast majority of such cells from the colonic mucosa (up to 96% of CD4⁺CCR5⁺). Absence of CCR5-expressing cells from blood endured for at least 1 week, while CCR5⁺ cells in colon were substantially replenished over the same time span. These data open an avenue to investigation of combined early ART treatment and CCR5⁺ reservoir depletion for cure of HIV-infected infants.