Abstract: Human herpesvirus-6 (HHV-6) infects the majority of children under the age of 2 years causing roseola infantum. Following short self-limited disease, the virus enters into a latency phase in peripheral blood lymphocytes (PBL). It has been previously reported that HHV-6 reactivation from latency, in immunocompromised patients undergoing bone marrow transplantation (BMT), could result in febrile illness, pneumonitis, meningitis, and/or encephalitis. In our study, 14 BMT patients received two different antiviral prophylactic therapies: 8 patients received acyclovir, whereas 6 patients received ganciclovir. Clinical manifestations and virus recovery were monitored pre- and post-BMT by polymerase chain reaction tests of cord blood cells cultured with the patients' PBL. No HHV-6 recovery was shown in the 6 patients treated with ganciclovir, whereas 3 of the 8 acyclovir-treated patients experienced virus reactivation 20–21 days post-BMT. One of the 3 patients was asymptomatic but had late engraftment; the second patient had prolonged fever, skin rash, and hemorrhage; the third patient experienced prolonged fever, pneumonitis, marrow rejection, and fatal encephalitis. It is concluded that viral reactivation may be prevented by prophylactic treatment with ganciclovir. Our observation awaits further documentation in prospective randomized trials in high-risk BMT recipients.