Renal allograft rejection episodes are frequent in children and often lead to allograft failure. Frequent association of fever with rejection in our transplant program provoked a prospective evaluation of concurrent infection during rejection episodes. Because cytomegalovirus has an established role in rejection and allograft survival, evaluation of cytomegalovirus and other herpes viruses (human simplex virus type 1, varicella, Epstein-Barr virus, and human herpes virus type 6 [HHV-6]) was undertaken in addition to standard bacterial investigation. A total of 37 patients were followed over a 30-month period. Six of eight rejection episodes were associated with herpes viruses (HHV-6, n = 6, and Epstein-Barr virus, n = 1). Three of the herpes-group-associated rejection episodes were treated with antiviral therapy in addition to pulse steroid treatment, with full recovery. The three patients with HHV-6-associated rejection episodes who were treated with pulse steroids, but no antiviral therapy, developed chronic allograft rejection. The recipient's response to allograft antigens may be influenced by concomitant herpes infection, and specific antiviral therapy appears to be indicated when infection is confirmed in association with rejection. An antiviral treatment program coupled with modulation of standard antirejection immunotherapy has the potential to improve morbidity and mortality in the pediatric renal transplant population.