Fifteen cases of cimetidine-associated mental confusion have recently appeared. To further study this syndrome, we monitored cimetidine serum concentrations in 36 patients and correlated these with changes in mental status. Thirty patients did not change on cimetidine and 6 experienced moderate to severe mental status changes. These 6 patients had both renal and liver dysfunction (p less than 0.05), as well as cimetidine trough concentrations above 1.25 micrograms/ml (p less than 0.05), in close association with mental status changes. The changes in mental status became progressively more severe as trough concentrations rose. Five patients underwent lumbar punctures. The cerebrospinal fluid to serum ratio of 0.24:1 indicates that cimetidine passes the blood-brain barrier, and this raises the possibility that mental status changes are due to blockade of central nervous system histamine H2 receptors. Our studies identify a subgroup at high risk for both elevated troughs and mental confusion. These patients with severe compromise of both renal and hepatic excretory systems must be closely observed and given reduced cimetidine doses if side effects are to be avoided.