Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11-E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150 −/− but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150 −/− cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150 −/− cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses. M easles virus (MV), a member of the family Paramyxoviridae, infects more than 10 million persons worldwide each year, resulting in several hundred thousand deaths (1, 2). A serious complication is the persistent infection of the CNS known as subacute sclerosing panencephalitis (SSPE) that occurs at a frequency of 4-11 cases per 100,000 cases of MV infection. SSPE is a progressive fatal neurodegenerative disease with characteristic features of replication of MV in neurons in the presence of high titers of MV antibodies, modest infiltration of T and B cells into the CNS, and replication of defective MV in the CNS with biased mutation of U-to-C and A-to-G in the viral genome (3-5). These hypermutations occur primarily in the matrix (M) gene but are also observed to a lesser extent in the fusion (F) and hemagglutinin (H) genes (3, 4). A transgenic mouse model that expresses the human MV receptor CD46 recapitulates all the features of SSPE on infection with MV, with biased hypermutations of U-to-C and A-to-G accounting for more than 95% of point mutations in the M gene (3,4,6). Interestingly, these biased hypermutations play a direct role in the pathogenesis of SSPE by facilitating a significant prolongation of MV persistence within the CNS, as opposed to mere accumulation as a result of persistent infection (7). In support of a direct role of M gene hypermutations in the establishment of SSPE, MV generated by reverse genetics and containing a hypermutated M...