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Summary: Zaire Ebola virus (ZEBOV) survivors experience visual and CNS sequelae that suggests the ZEBOV glycoprotein can mediate neurotropism. Replication-competent rVSVΔG-ZEBOV-GP vaccine candidate is generally well tolerated; however, its potential neurotropism requires careful study. Here, we show that a single inoculation of rVSVΔG-ZEBOV-GP virus in neonatal C57BL/6 mice results in transient viremia, neurological symptoms, high viral titers in eyes and brains, and death. rVSVΔG-ZEBOV-GP infects the inner layers of the retina, causing severe retinitis. In the cerebellum, rVSVΔG-ZEBOV-GP infects neurons in the granular and Purkinje layers, resulting in progressive foci of apoptosis and neurodegeneration. The susceptibility to infection is not due to impaired type I IFN responses, although MDA5−/−, IFNβ−/−, and IFNAR1−/− mice have accelerated mortality. However, boosting interferon levels by co-administering poly(I:C) reduces viral titers in CNS and improves survival. Although these data should not be directly extrapolated to humans, they challenge the hypothesis that VSV-based vaccines are non-neurotropic. : Survivors of Ebola infections can experience neurologic and ocular symptoms, raising some concern that replication-competent vaccines expressing Ebola components could infect neurons in susceptible subjects. McWilliams et al. show that the rVSVΔG-EBOV-GP pseudovirus infects neurons in the eyes and brains of neonatal mice, causing tissue damage and lethality. Keywords: Ebola virus, ebolavirus, filovirus, Ebola glycoprotein, VSV, pseudotyped virus, VSV vaccine, innate immunity, neurotropism, neurovirulence, Ebola vaccine