HIV infection causes rapid and lasting defects in the population of Vgamma2Vdelta2 T cells. To fully describe the impact of HIV, we examined PBMC samples from HIV+ patients receiving highly active antiretroviral therapy, who had displayed prolonged viral control and CD4 counts above 300 cells/mm3. We observed lower frequencies of CD27-/CD45RA- Vgamma2Vdelta2 cells in HIV+ individuals when compared with controls, coupled with an increased proportion of CD45RA+ cells. These changes were common among 24 HIV+ patients and were not related to CD4 cell count or viral RNA burden. Vgamma2 cells from HIV+ individuals had lower expression of Granzyme B and displayed reduced cytotoxicity against Daudi targets after in vitro stimulation. There was increased expression of FasR (CD95) on Vgamma2 cells from HIV+ PBMC that may be a mechanism for depletion of Vgamma2 cells during disease. In addition to the well-characterized defects in the Vgamma2 repertoire and functional responses to phosphoantigen, the proportion of CD27-/CD45RA- Vgamma2Vdelta2 T cells after isopentenyl pyrophosphate stimulation was reduced sharply in HIV+ donors versus controls. Thus, HIV infection has multiple impacts on the circulating Vgamma2Vdelta2 T cell population that combine to reduce the potential effector activity in terms of tumor cytotoxicity. Changes in Vgamma2Vdelta2 T cells, along with concomitant effects on NK and NKT cells that also contribute to tumor surveillance, may be important factors for elevating the risk of malignancy during AIDS.