ADV has emerged as an important pathogen in children undergoing allogeneic HPCT. A prospective study of the epidemiology of ADV infection and preemptive therapy of high risk ADV infections in children undergoing HPCT was undertaken. Cultures of throat, urine, and stool for viral pathogens and plasma for ADV PCR were obtained prior to transplantation, weekly for the first 100 days, and then monthly for one yr. Children developing high-risk ADV infections were treated preemptively with cidofovir 1 mg/kg/day given three times weekly for three wk. A case-controlled study was performed to identify risk factors for high-risk ADV infections. Seven (18%) of the 38 subjects developed high-risk ADV infections usually within 100 days of HPCT and were preemptively treated with i.v. cidofovir at a dose of 1 mg/kg/dose three times weekly for nine doses. High-risk ADV infections resolved in all seven patients without renal toxicity. CMV viremia occurred in two of seven patients during or shortly after therapy with cidofovir. A case-control study did not identify any risk factors that achieved statistical significance. Treatment with a modified dosing regimen of cidofovir was well-tolerated and high-risk ADV infections resolved in all patients.