Objective: To evaluate the efficacy and safety of ganciclovir therapy in neonates with congenital cytomegalovirus (CMV) disease. Study design: Neonates with symptomatic CMV disease involving the central nervous system were randomly assigned to receive 6 weeks of intravenous ganciclovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points). Results: From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 ganciclovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P = .06). None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P < .01). A total of 43 patients had a BSER at both baseline and at 1 year or beyond. Five (21%) of 24 ganciclovir recipients had worsening of hearing between baseline and ≥1 year versus 13 (68%) of 19 control patients (P < .01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P < .01). Conclusions: Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at ≥1 year. Almost two thirds of treated infants have significant neutropenia during therapy.