The relative contribution of human cytomegalovirus (HMCV)–specific CD4⁺ and CD8⁺ T cells to the control of HCMV infection in hematopoietic stem cell transplant (HSCT) recipients is still controversial. HCMV reactivation and HCMV-specific CD4⁺ and CD8⁺ T cell reconstitution were monitored for 1 year in 63 HCMV-seropositive patients receiving HSCT. HCMV reactivation was detected in all but 2 patients. In 20 of 63 (31.7%) patients (group 1) HCMV infection resolved spontaneously, whereas 32 of 63 (50.8%) patients (group 2) controlled the infection after a single short-course of pre-emptive therapy and the remaining 9 (14.3%) patients (group 3) suffered from relapsing episodes of HCMV infection, requiring multiple courses of antiviral therapy. The kinetics and magnitude of HCMV-specific CD8⁺ T cell reconstitution were comparable among the 3 groups, but HCMV-specific CD4⁺ T cells were lower in number in patients requiring antiviral treatment. HCMV-seronegative donors, as well as unrelated donors (receiving antithymocyte globulin) and acute graft-versus-host disease (GVHD) were associated with both delayed HCMV-specific CD4⁺ T cell reconstitution and severity of infection. Conversely, these risk factors had no impact on HCMV-specific CD8⁺ T cells. Eight patients with previous GVHD suffered from HCMV gastrointestinal disease, although in the presence of HCMV-specific CD4⁺ and CD8⁺ systemic immunity and undetectable HCMV DNA in blood. Reconstitution of systemic HCMV-specific CD4⁺ T cell immunity is required for control of HCMV reactivation in adult HSCT recipients, but it may not be sufficient to prevent late-onset organ localization in patients with GVHD. HCMV-specific CD8⁺ T cells contribute to control of HCMV infection, but only after HCMV-specific CD4⁺ T cell reconstitution.