Arabinosyl cytosine (ara-C) inhibits the replication of rabies virus strains in all tissue culture cell systems tested, including the BHK-21, RK 13, and WI-38 cell lines. The growth of other RNA-containing viruses (Egtved, NDV, West Nile, Sindbis, WEE, LCM, Reo type 1, and Mengo) is not significantly affected by the antimetabolite, although the infective titers of both the Indiana and New Jersey serotypes of VSV and cocal virus are reduced 2- to 20-fold under the conditions used. When actinomycin D, nogalamycin, cycloheximide, or puromycin are added during the first 3 hours of rabies viral replication in BHK-21 cells in the presence of ara-C, the inhibitory effect of the pyrimidine nucleoside analog is partially or completely reversed. The data are consistent with the hypothesis that ara-C requires the induction of a cellular protein for its specific inhibitory action on rabies virus growth, and that this protein exerts its inhibitory effect at an early stage in viral replication.