Abstract: Objective To observe the efficacy and safety of oral valganciclovir (VGCV)in newborns with congenital cytomegalovirus (CMV)infection. Methods A total of 48 newborns with congenital CMV infection were randomly divided into a VGCV group and a ganciclovir(GCV) group (n=24 each) using random number table method. The VGCV group were treated with oral VGCV, 16 mg/kg, q12h, while the GCV group received intravenous injection of GCV, 6 mg/kg, q12h. The course of treatment was 6 weeks for both groups. Blood and urine CMV load, serum CMV-IgM, hepatosplenomegaly, hyperbilirubinemia, cranial MRI, choroidal retinitis, brainstem auditory evoked potential, and neutropenia were observed and compared between the two groups. The peripherally inserted central catheter (PICC) placement rate, length of stay, and hospitalization costs were also compared between the two groups. Results No significant differences were observed regarding the therapeutic effect of neonatal congenital CMV infection as well as the incidence of neutropenia during treatment between the VGCV group and GCV group (P>0.05). The length of stay of the VGCV group was shorter than that of the GCV group, the hospitalization expenses were lower than those of the GCV group, and the PICC placement rate was significantly lower than that of the GCV group (P<0.05). Conclusions The efficacy and adverse reactions of oral VGCV and intravenous drip of GCV in the treatment of neonatal congenital CMV infection are similar. However, oral administration of VGCV can shorten length of stay, reduce medical expenses and PICC placement rate.