The documented link between mTORi medication and a decreased incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains unclear. The frequency of CMV infection and T-cell profile in KTRs treated with mTORis, and mycophenolic acid (MPA) were compared in the study, and in vitro mTORi effects on T-cell phenotype and functions were investigated. Both αβ and γδ T cells revealed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 after transplantation in the 16 KTRs with severe CMV infection, compared to the 17 KTRs without or with spontaneously resolving CMV infection in R+ KTRs treated with MPA. When compared to individuals treated with MPA (n=44), the proportion of PD-1+ and CD85j+ αβ and γδ T cells dropped in patients treated with mTORis (n=27), as did the incidence and severity of CMV infections. Treatment with mTORi significantly increased the proportions of late-differentiated and cytotoxic αβ T cells, as well as IFN-producing and cytotoxic γδ T cells. In vitro, mTORis improved T cell proliferation, viability, and CMV-induced IFNγ production while decreasing PD-1+ and CD85j+ expression, shifting T cells to a more efficient EOMESlow Hobithigh profile. The mTORi impact was linked to enhanced TCR signaling in γδ T cells. Severe CMV replication was linked to a defective T-cell profile, and mTOR improved T-cell fitness while also controlling CMV. A malfunctioning T-cell phenotype might be used as a novel biomarker to predict post-transplantation infection and stratify individuals who would benefit from mTORi therapy.