Two inbred strains of mice were used in this study, the C57BL/6J which is reported to be a high interferon producer and the C3H/HeJ which is reported to be a low interferon producer. Each mouse received a single i.p. injection of either Newcastle disease virus (NDV) or the double-stranded nucleotide, polyinosinic acid-polycytidilic acid (poly (rI.rC], both type I interferon inducers, or cadmium chloride, a known inducer of metallothionein (MT), and were killed 24-hr later. Treatment of the C57BL and C3H mice with 1 mg Cd/kg caused a 14- and 16-fold increase in hepatic MT concentrations, respectively. In both strains, this induction was accompanied by an increase in the hepatic concentration of zinc but not copper. There were no observed changes in the circulating levels of interferon. In the C57BL mice, both the administration of poly (rI.rC), at a dose of 10 mg/kg, and NDV, at a dose of 512 hemagglutinating units/mouse, produced a 4-fold increase in the hepatic concentration of MT. Although both treatments caused an increase in levels of interferon, the increase seen with NDV was greater than that seen with poly (rI.rC). In the C3H mice, the results were quite different. Although both treatments induced hepatic MT concentrations 4- to 5-fold, the increase in interferon levels observed following the administration of poly (rI.rC) was higher than that seen with NDV and some 50-fold higher than the increase produced by the polynucleotide in the C57BL mice. The results of this study indicate that two interferon-inducing agents, poly (rI.rC) and NDV, are also capable of inducing hepatic metallothionein.