Patients with Wilson's disease often have a further increase in hepatic copper when given zinc as an initial treatment, although there is no associated clinical deterioration. To better understand this situation an animal model was developed in which copper-loaded rats are treated with zinc administered subcutaneously. In the presence of equal amounts of copper loading in liver, control rats show hepatic damage but zinc-treated rats do not. Zinc-treated rats have much higher levels of hepatic metallothionein. Gel filtration studies reveal that much of the hepatic copper in zinc-treated rats is in this metallothionein fraction, whereas the copper in control animals is primarily associated with fractions of high or low molecular weight. Subcutaneous zinc therapy also induces intestinal, but not brain, metallothionein. We interpret these findings to indicate that zinc therapy protects against copper toxicity in liver by induction of hepatic metallothionein, which sequesters copper in a nontoxic form.