CD4 T lymphocytes expressing CD8dim (DP: CD4 CD8dim) or NKG2D represent cytotoxic effector populations, which have been involved in viral infections and chronic diseases. The frequency of DP cells was analyzed by flow cytometry in 300 consecutive HIV-infected patients and 50 healthy controls. NKG2D expression and memory/effector markers in CD4 T cells were also studied, in addition to virologic and genetic factors involved in DP T-cell expansion. HIV-infected patients showed a significantly higher frequency of DP cells than controls, mainly in patients with advanced disease. Expansion of DP cells was related to NKG2D appearance in CD4 T cells and was predicted by CD4 CD28null T-cell levels. Cells expressing CD8dim and NKG2D cells are closely related populations with a similar pattern of surface markers, perforin expression, and responses to activation. We also found that these subsets seem to share an ontogenic relationship and TcR oligoclonality. In this way, cytomegalovirus infection and certain HLA alleles, such as DR7, conditioned the expansion of DP cells. Their common ontogenic origin and oligoclonality, possibly due to repeated encounters with the same antigen, could result in a limitation of the repertoire of responder cells and in a worse prognosis of HIV infection.