HIV infection is associated with immune dysfunction, perturbation of immune-cell subsets and opportunistic infections. CD161⁺⁺CD8⁺ T cells are a tissue-infiltrating population that produce IL17A, IL22, IFNγ, and TNFα, cytokines important in mucosal immunity. In adults they dominantly express the semi-invariant TCR Vα7.2, the canonical feature of mucosal associated invariant T (MAIT) cells and have been recently implicated in host defense against pathogens. We analyzed the frequency and function of CD161⁺⁺/MAIT cells in peripheral blood and tissue from patients with early stage or chronic-stage HIV infection. We show that the CD161⁺⁺/MAIT cell population is significantly decreased in early HIV infection and fails to recover despite otherwise successful treatment. We provide evidence that CD161⁺⁺/MAIT cells are not preferentially infected but may be depleted through diverse mechanisms including accumulation in tissues and activation-induced cell death. This loss may impact mucosal defense and could be important in susceptibility to specific opportunistic infections in HIV.