There is sufficient evidence for pulmonary carcinogenicity of inhaled cadmium (Cd) compounds in rats whereas no such evidence was found in mice and hamsters, indicating significant species differences in the pulmonary response to inhaled Cd. We hypothesized that expression of metallothionein (MT) protein in the lung after inhalation of Cd differs between species thereby providing different degrees of sequestration of Cd and protection from its effects. Rats and mice were exposed to 100 micrograms CdCl2 aerosols/m3 for 4 weeks, and the presence of MT was determined in lung and free lung cell homogenates as well as by immunocytochemistry in lung sections up to 28 days post-exposure. Cd exposure significantly increased MT in homogenates of total lung in both species; however, no significant increase of MT in rat lung tissue after removal of free lung cells by lavage was found whereas MT was still significantly increased in lavaged mouse lung tissue throughout the post-exposure time. Histochemical analysis of lung sections revealed that mainly the epithelial cells of the bronchi, bronchioli and alveoli of Cd-exposed mice expressed MT. Baseline MT levels were also greater in the lungs of mice compared to rats. The retained Cd dose per g lung was about 2-fold greater in mice. The greater MT induction upon exposure to the same inhaled Cd concentration and the greater baseline MT levels may offer an explanation for the resistance of mice towards the pulmonary carcinogenic effect of inhaled Cd.