Successful and sustained CD4 T-cell reconstitution is associated with increased survival after hematopoietic cell transplantation (HCT), but opportunistic infections may adversely affect the time and extent of immune reconstitution. Human herpesvirus 6B (HHV-6B) efficiently infects CD4 T cells and utilizes as a receptor CD134 (OX40), a member of the TNF superfamily that antagonizes regulatory T-cell (T) activity. Reactivation of HHV-6B has been associated with aberrant immune reconstitution and acute graft-versus-host disease (aGVHD) after HCT. Given that T counts are negatively correlated with aGVHD severity, we postulate that one mechanism for the poor CD4 T-cell reconstitution observed shortly after transplant may be HHV-6B infection and depletion of peripheral (extra-thymic) CD4 T cells, including a subpopulation of T cells. In turn, this may trigger a series of adverse events resulting in poor clinical outcomes such as severe aGVHD. In addition, recent evidence has linked HHV-6B reactivation with aberrant CD4 T-cell reconstitution late after transplantation, which may be mediated by a different mechanism, possibly related to central (thymic) suppression of T-cell reconstitution. These observations suggest that aggressive management of HHV-6B reactivation in transplant patients may facilitate CD4 T-cell reconstitution and improve the quality of life and survival of HCT patients.