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CCR5 is thought to play a central role in orchestrating migration of cells in response to inflammation. CCR5 antagonists can reduce inflammatory disease processes, which has led to an increased interest in using CCR5 antagonists in a wide range of inflammation-driven diseases. Paradoxically, these antagonists appear to function without negatively affecting host immunity at barrier sites. We reasoned that the resolution to this paradox may lie in the CCR5 + T cell populations that permanently reside in tissues. We used a single-cell analysis approach to examine the human CCR5 + T cell compartment in the blood, healthy, and inflamed mucosal tissues to resolve these seemingly contradictory observations. We found that 65% of the CD4 tissue-resident memory T (TRM) cell compartment expressed CCR5. These CCR5 + T RM cells were enriched in and near the epithelial layer and not only limited to T H 1-type cells but also contained a large T H 17-producing and a stable regulatory T cell population. The CCR5 + T RM compartment was stably maintained even in inflamed tissues including the preservation of T H 17 and regulatory T cell populations. Further, using tissues from the CHARM-03 clinical trial, we found that CCR5 + T RM are preserved in human mucosal tissue during treatment with the CCR5 antagonist Maraviroc. Our data suggest that the human CCR5 + T RM compartment is functionally and spatially equipped to maintain barrier immunity even in the absence of CCR5-mediated, de novo T cell recruitment from the periphery., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)