T cells recognizing self-peptides are typically deleted in the thymus by negative selection. It is not known whether T cells against persistent viruses (eg, herpesviruses) are generated by the thymus (de novo) after the onset of the infection. Paptides from such viruses might be considered by the thymus as self-peptides, and T cells specific for these peptides might be deleted (negatively selected). Here we demonstrate In baboons infected with baboon cytomegalovirus and baboon lymphocryptovirus (Epstein-Barr virus-like virus) that after autologous transplantation of yellow fluorescent protein (YFP)-marked hematopoietic cells, YFP+ CD4 T cells against these viruses were generated de novo. Thus the thymus generates CD4 T cells against not only pathogens absent from the host but also pathogens present in the host. This finding provides a strong rationale to improve thymopoiesis in recipients of hematopoletic cell transplants and, perhaps, in other persons lacking de nova-generated CD4 T cells, such as AIDS patients and elderly persons.