Cimetidine, an antagonist to histamine H2-receptors, reportedly lowers serum calcium and/or serum immunoreactive parathyroid hormone (iPTH) concentrations in some patients with primary and secondary (azotemic) hyperparathyroidism. We administered the drug orally (300 mg every 6 h) to five normal volunteers and four azotemic patients with secondary hyperparathyroidism who were not undergoing chronic hemodialysis. The normal persons and one azotemic patient took the drug for 5 weeks, and the remaining azotemic patients took it for 1 week. Before treatment, all patients had elevated levels of serum iPTH (two different assay systems), with or without elevated serum calcium concentrations, and increased urinary excretion of cAMP (per 100 ml glomerular filtrate). Cimetidine treatment caused no changes in serum calcium, phosphorus, or iPTH or in urinary cAMP (expressed as nanomoles per g creatinine). Serum creatinine, however, increased significantly in patients (P less than 0.02) and control subjects (P less than 0.025), which yielded statistically significant but spurious increases of urinary cAMP when expressed per 100 ml glomerular filtrate. We conclude that short term cimetidine administration has no effect on parathyroid function in normal persons or those with azotemic hyperparathyroidism. Because of its confusing effect on serum creatinine and a possible (albeit rare) adverse effect on renal function, the drug should be used with caution in azotemic patients not yet requiring chronic dialysis.