Effective CD8 T-cell responses play an important role in determining the course of SIV/HIV viral infection. Here we identified a unique population of dysfunctional CD8 T-cells in lymphoid tissues and bronchoalveolar lavage (BAL) of rhesus macaques with chronic SIV infection characterized by co-expression of CD6 and PD-1. The frequency of CD6 and PD-1 co-expressing CD8 T-cells was significantly increased in lymphoid tissues and BAL during chronic SIV infection compared to pre-infection levels. These CD6PD-1CD8 T-cells displayed impaired proliferation, cytokine secretion and cytotoxicity compared to their CD6PD-1CD8 T cell counterparts. The frequency of CD8PD-1 and CD8CD6PD-1 T-cells in the lymph node and bone marrow did not correlate with SIV viral load, whereas the frequency of CD8CD6PD-1 T-cells positively correlated with SIV viral load in these tissues highlighting the contribution of CD6 to disease progression. CD6PD-1CD8 T-cells expressed elevated levels of SHP2 phosphatase compared to CD6PD-1CD8 T-cells providing a potential mechanism by which CD6 may induce T-cell dysfunction during chronic SIV infection. Combined targeting of CD6 and PD-1 effectively revived the CD8 T-cell proliferative response suggesting a strategy for potential therapeutic benefit.