Adult but not newborn mice bearing the allele M chi display a specific resistance to in vivo infection with orthomyxoviruses. In vitro, cells isolated from adult M chi-animals exhibit a several hundred-fold higher sensitivity to the action of interferon (IFN) against influenza viruses than do cells from M chi-negative mice. We here tested whether or not cells from immature M chi-bearing animals would likewise express the virus-specific higher sensitivity to IFN. Cultured cells from 16-day gestation mouse embryos with and without M chi were equally permissive for an influenza virus when single cycle virus growth was measured. However, influenza virus plaques were smaller in M chi-cells. Treatment of cells with mouse interferon reduced viral protein synthesis, single cycle virus yields and the number of virus plaques more efficiently in M chi-cells than in non-M chi-cells. The smaller size of influenza virus plaques in M chi-cells not treated with IFN seems to be due to the action of endogenous IFN:inclusion of anti-interferon antibodies in the agar overlay during plaque formation resulted in plaques of approximately the size seen in control cells. When treated with the same dose of IFN, cells with M chi developed protection against influenza virus more rapidly than cells without M chi. However, after removal of IFN, the antiviral protection decayed more rapidly in cells in cells without M chi. No differences in sensitivity to IFN, viral plaque formation and kinetics of induction and decay of the antiviral state were observed between the two cell types when the rhabdovirus VSV was used as challenge. Thus, the allele M chi is expressed in cultured embryo cells much as in cells from adult animals, and susceptibility of newborn M chi-animals to influenza virus infection cannot be due to inability of their cells to respond to IFN appropriately.