Cimetidine is a histamine H2-receptor antagonist that is used in the treatment of patients with gastric and duodenal ulcers and other hypersecretory conditions. This drug has a structure that suggests that it could act as a chelating agent. To examine its effects on trace metal and mineral metabolism, 38 weanling male Sprague-Dawley rats were assigned to one of five treatment groups. These were a high dose [(HD) 1750 mg/(kg X d)] group, HD pair-fed control (HDPF) group, intermediate dose [(ID) 875 mg/(kg X d)] group, ID pair-fed (IDPF) group and low dose [(LD) 87.5 mg/kg X d)] group. In a separate experiment, 20 female Sprague-Dawley rats were assigned to one of two treatment groups: a high dose cimetidine group [(HDFem) 1750 mg/kg X d)] and a pair-fed control group (PFFem). Cimetidine was administered intragastrically four times per week for 5 wk. Significant differences (P less than 0.05) found among groups for the male rats studied included higher plasma copper in the HD and the ID groups, higher plasma sodium, liver copper, heart calcium and heart zinc in the HD group and a lower percentage of fecal excretion of all the divalent metals studied in the HD and the ID groups than in their pair-fed controls. Pathologic examination of the liver revealed extensive fatty infiltration of liver cells, liver cell necrosis and disrupture of liver lobular architecture in the HD group. Cimetidine-dosed females had higher zinc in heart and plasma, higher copper in heart, kidney, liver, jejunum, ileum and uterus, higher manganese in stomach and ileum, lower iron in kidney and liver, lower kidney calcium and higher stomach calcium and lower liver magnesium compared with their pair-fed controls. Levels of liver and kidney metallothionein in the two groups were comparable. Male and female rats receiving high dose cimetidine experienced significant changes in tissue concentrations of some of the trace metals and minerals studied.