Cytomegalovirus (CMV) reactivation may lead to CMV disease associated with high morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT); the identification of clinically relevant markers may aid in the identification of patients at increased risk for developing CMV-associated complications. We evaluated the phosphorylation of signal transducer and activator of transcription 5 (STAT5) in CD4+ T cells, CD8+ T cells, and TCRγδ T cells in response to stimulation with IL-7 or IL-2 after HSCT by analyzing blood samples taken monthly 1 to 6 months after HSCT. Patients were monitored weekly with a quantitative PCR from the time of engraftment for CMV viral load in whole blood until at least day 100 after HSCT. We identified a correlation between clinical outcome regarding CMV replication and the ability to respond to IL-7 and IL-2 defined by STAT5 phosphorylation (pSTAT5). Patients with recurrent or prolonged CMV replications had significantly lower pSTAT5 upon stimulation of T cells with either IL-7 or IL-2 at time points 1 through 3 than those without CMV replication (P < .05). This was also found after stimulation of CD8+ T cells at time point 2 (P < .05). We conclude that reduced responses to IL-7, reflected by pSTAT5, may represent a clinically relevant functional biomarker for individuals at increased risk for CMV reactivation; our data may also aid in designing better strategies to improve anti-CMV immune responses without increasing the risk of developing graft-versus-host disease.