A striking radioresistance has been found in mice which were subjected to various pretreatments to induce metallothionein synthesis in the liver prior to irradiation. The tolerance to lethal damage from an LD50 level of radiation during a 30-day postirradiation period was demonstrated by a highly significant difference (P less than 0.01) in mortality rate between mice given subcutaneously manganese, cadmium, or zinc injection or surgical skin excision of mice and the control mice (no pretreatment). A typical loss in body weight that generally reached a peak 2 weeks after irradiation was observed in the control mice, but mice given a dose of 10 mg manganese per kilogram body weight showed a steady weight increase even a few days after irradiation. The normal level of metallothionein in mouse liver is 20 micrograms/g tissue. This level increased up to 70 micrograms/g tissue following irradiation at 6.3 Gy. Among irradiated mice, metallothionein levels in the liver increased approximately 200-800% after cadmium, manganese, or zinc injection compared to levels of irradiated mice without pretreatment. Mice undergoing 2 X 2-cm2 dermal excision also demonstrated a similar reduction of mortality and high metallothionein contents in liver, i.e., 150-400 micrograms/g. The present results, together with our previous findings (Matsubara et al., 1982, 1983, 1984; Matsubara, 1986), suggest that the body's protective mechanism against radiation strongly correlates with the biosynthesis of metallothionein or metallothionein itself acting as a scavenger of radiation-induced peroxides.