The CD8(+) T cell compartment of human CMV-seropositive individuals characteristically contains a high proportion of cells that express NK cell receptors (NKRs) which may contribute to the surveillance of virus-infected cells. To test whether this enhanced expression is a direct and immediate result of CMV infection, we used DNA microarrays to analyze putative changes in the RNA expression level of 39 NKRs in CMV-specific CD8(+) T cells of renal transplant recipients experiencing primary CMV infection. Already in the acute phase of infection 29 NKRs were induced, of which 19 remained high 1 year after cessation of viral replication. Activating and inhibitory NKRs were induced to a similar extent. Detailed longitudinal flow cytometric analyses confirmed NKR changes at the protein level. Strikingly, a strong induction of CD94 on CD3(+) T cells was observed with surface expression of activating CD94(dim) NKG2C dimers appearing before inhibitory CD94(bright) NKG2A ones. After the acute phase of infection, the balance between inhibitory and activating receptors did not change. Thus, CMV infection induces a rapid and lasting change in the expression of NKRs on human CD8(+) T cells.