Adult lethal milk (lm/lm) mutant mice display increased induction of hepatic metallothionein synthesis compared to wild-type mice following the subcutaneous injection of 40 mumol ZnCl2/kg mouse. At this zinc dose the rate of incorporation of [35S] cysteine into hepatic metallothionein in adult (100- to 230-day-old) lm/lm mice was approximately 2.4-fold greater than the rate of incorporation of isotope in wild-type animals. At a higher zinc dose (160 mumol ZnCl2/kg) the incorporation of [35S] cysteine into hepatic metallothionein was similar in lm/lm and wild-type mice. The altered dose-response to zinc administration was not due to a change in hepatic zinc, copper, or manganese levels, to a difference in 65Zn uptake, or to an alteration in 65Zn bound to differential centrifugation fractions of adult lm/lm liver. 65Zn bound to hepatic metallothionein was, however, increased in aging lm/lm mice with symptomatic skin lesions.