Summary The aim of this study was to characterize timing, kinetic, and magnitude of CMV‐specific immune response after hematopoietic stem cell transplantation (HSCT) and its ability to predict CMV replication and clinical outcomes. Using cell surface and intracellular cytokine staining by flow cytometry, CMV‐specific T‐cell response was measured in blood, while CMV viral load and chimerism were determined by real‐time PCR. Patients that reconstituted CMV‐specific T‐cell response within 6 weeks after Allo‐SCT showed a more robust immune response (CD8+: 0.7 cells/μl vs. 0.3/μl; P‐value = 0.01), less incidence of CMV replication (33% vs. 89.5%; P‐value = 0.007), reduced viral loads (1.81 log copies/ml vs. 0 copies/ml; P‐value = 0.04), and better overall survival (72%; CI: 0.53–0.96 vs. 42% CI: 0.24–0.71; P‐value = 0.07) than patients with a delayed immune reconstitution. Viremic patients had significantly higher transplant‐related mortality than nonviremic patients after 1 year (33% CI: 0.15–0.52 vs. 0% CI: 0.05–0.34; P‐value = 0.01). Risk factors independently associated with viral replication were receptor pretransplant CMV‐positive serostatus (P‐value = 0.02) and acquiring CMV‐specific T‐cell response after 6 weeks post‐transplantation (P‐value = 0.009). In conclusion, timing of acquiring a positive CMV‐specific T‐cell immune response after transplantation may identify patients with different risk for viral replication and different clinical outcomes, including survival.