Zinc is an essential heavy metal for the normal function of the central nervous system (CNS), but the knowledge of its metabolism and functions is scarce. In this report we have studied the effect of a zinc deficient diet on the regulation of brain metallothioneins (MTs). In situ hybridization analysis revealed that brain MT-I induction by restraint stress was significantly blunted in some but not all brain areas in the mice fed the zinc deficient diet compared to normally fed mice. In contrast, brain MT-I induction by the administration of bacterial lipopolysaccharide (LPS) was not significantly lower in the mice fed the zinc deficient diet. In contrast to MT-I, MT-III mRNA levels were minimally affected by either stress or LPS. Yet, significant decreasing effects of the zinc deficient diet were observed in areas such as the neocortex, CA1-CA3 neuronal layer and dentate gyrus of the hippocampus, and the Purkinje neuronal layer of the cerebellum. These results demonstrate that dietary zinc deficiency impairs the response of brain MTs during both stress and LPS-elicited inflammatory response in a highly specific manner.