Abstract Background Ganciclovir protects against hearing deterioration in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system (CNS). Objectives To assess the neurodevelopmental impact of ganciclovir therapy in this population. Study design 100 neonates were enrolled into a controlled Phase III study of symptomatic congenital CMV involving the CNS, and were randomized to either 6 weeks of intravenous ganciclovir or no treatment. Denver developmental tests were performed at 6 weeks, 6 months, and 12 months. For each age, developmental milestones that ≥90% of normal children would be expected to have achieved were identified. The numbers of milestones not met (“delays”) were determined for each subject. The average number of delays per subject was compared for each treatment group. Results At 6 months, the average number of delays was 4.46 and 7.51, respectively, for ganciclovir recipients and “no treatment” subjects ( p = 0.02). At 12 months, the average number of delays was 10.06 and 17.14, respectively ( p = 0.007). In a multivariate regression model, the effect of ganciclovir therapy remained statistically significant at 12 months ( p = 0.007). Conclusions Infants with symptomatic congenital CMV involving the CNS receiving intravenous ganciclovir therapy have fewer developmental delays at 6 and 12 months compared with untreated infants. Based on these data as well as the previously published data regarding ganciclovir treatment and hearing outcomes, 6 weeks of intravenous ganciclovir therapy can be considered in the management of babies with symptomatic congenital CMV disease involving the CNS. If treatment is initiated, it should be started within the first month of life and patients should be monitored closely for toxicity, especially neutropenia. Since existing data only address the treatment of symptomatic congenital CMV disease involving the CNS, these data cannot be extrapolated to neonates with other manifestations of CMV disease, including asymptomatic babies and symptomatic babies who do not have CNS involvement.