Rats subjected to chronic immobilization stress showed a reduced serum metallothionein (MT) response to acute immobilization stress compared to nonchronically stressed rats. In contrast, liver MT response to acute immobilization stress was not influenced by previous chronic immobilization stress. These results suggest that serum MT levels are likely under endocrine regulation and that they do not reflect directly liver MT levels. Instead it appears that both MT pools are regulated differently. The fact that liver MT is resistant to adaptation to chronic stress may be related to its physiological function.