Reconstitution of T cell immunity is absolutely critical for the effective control of virus-associated infectious complications in hematopoietic stem cell transplant (HSCT) recipients. Coinfection with genetic variants of human cytomegalovirus (CMV) in transplant recipients has been linked to clinical disease manifestation; however, how these genetic variants impact T cell immune reconstitution remains poorly understood. In this study, we have evaluated dynamic changes in the emergence of genetic variants of CMV in HSCT recipients and correlated these changes with reconstitution of antiviral T cell responses. In an analysis of single nucleotide polymorphisms within sequences encoding HLA class I-restricted CMV epitopes from the immediate early 1 gene of CMV, coinfection with genetically distinct variants of CMV was detected in 52% of patients. However, in spite of exposure to multiple viral variants, the T cell responses in these patients were preferentially directed to a limited repertoire of HLA class I-restricted CMV epitopes, either conserved, variant, or cross-reactive. More importantly, we also demonstrate that longterm control of CMV infection after HSCT is primarily mediated through the efficient induction of stable antiviral T cell immunity irrespective of the nature of the antigenic target. These observations provide important insights for the future design of antiviral T cell-based immunotherapeutic strategies for transplant recipients, emphasizing the critical impact of robust immune reconstitution on efficient control of viral infection.