The effect of interferon on the replication of vesicular stomatitis virus (VSV) and type-C oncornavirus in two Balb/c mouse cell lines, JLS-V5 and JLS-V9R, infected with MuLV-R was examined. VSV replication was inhibited threefold (0-5 log10) in both cell lines by 10 to 20 units of interferon/ml. In JLS-V5 cells C-type virus yields, as measured by 3H-uridine incorporation and reverse transcriptase activity, were also reduced threefold by 10 to 20 units of interferon/ml. However, in JLS-V9R cells, C-type virus replication was refractory to interferon at concentrations up to 1 x 10(4) units/ml. Infectious C-type virus transmitted from JLS-V9R cells to Balb/3TS cells was as sensitive to interferon as virus transmitted from JLS-V5 cells, indicating that resistance of C-type virus in JLS-V9R cells is a feature of the cells rather than of the virus strain.