The basic nature of guanethidine and some of its effects suggested a possible action of this drug on histamine metabolism. A single intraperitoneal injection of guanethidine (10 mg/kg) in male rats was found to double the daily urinary excretion of free histamine; daily injection for three weeks caused a 10-fold increase. In male rats, guanethidine increased the number of mast cells in the peritoneal fluid and, in both peritoneal fluid and mesentery, caused a significant degranulation of these cells; this action was not observed in female rats. This finding may indicate that guanethidine blocks methylation of histamine by inhibiting imidazole methyl transferase since this enzyme is found in male but not in female rats. Bethanidine and reserpine had no effect on histamine excretion. Imidazole was found to be even more potent than guanethidine in causing an increase in urinary histamine. Guanethidine and imidazole neither potentiated nor mimicked the action of histamine on the isolated ileum.