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Summary: Elimination of lymphoid tissue reservoirs is a key component of HIV eradication strategies. CD8+ T cells play a critical role in control of HIV, but their functional attributes in lymph nodes (LNs) remain unclear. Here, we show that memory, follicular CXCR5+, and HIV-specific CD8+ T cells from LNs do not manifest the properties of cytolytic CD8+ T cells. While the frequency of follicular CXCR5+ CD8+ T cells was strongly inversely associated with peripheral viremia, this association was not dependent on cytolytic CXCR5+ CD8+ T cells. Moreover, the poor cytolytic activity of LN CD8+ T cells was linked to a compartmentalized dissociation between effector programming and the transcription factor T-bet. In line with this, activation of LN CD8+ T cells only partially induced the acquisition of cytolytic functions relative to peripheral blood CD8+ T cells. These results suggest that a state of immune privilege against CD8+ T cell-mediated cytolysis exists in lymphoid tissue, potentially facilitating the persistence of HIV. : Reuter et al. show that lymphoid tissue CD8+ T cells from HIV-infected and uninfected individuals do not possess phenotypic, functional, or transcriptional regulatory properties of cytolytic T cells equivalent to those found in circulation. Their findings suggest that the failure to eliminate HIV could be related to compartmentalized CD8+ T cell function favoring noncytolytic responses in lymphoid tissue. Keywords: HIV, lymphoid tissue, CD8+ T cells, cytotoxicity