Histamine plays a key role in the pathogenesis of chronic urticaria (CU). The authors of this paper have studied the effects of ingested histamine in 25 patients with CU. A 120 mg dose of histamine, well-tolerated in the healthy subject, was instillated into the duodenum. Concomitantly, plasma histamine (H) levels and plasma and urinary methylhistamine (MH) levels were measured. Intraduodenal administration of histamine was responsible for the development of an attack of urticaria in 64% of patients, while control subjects were asymptomatic. Plasma histamine levels were significantly higher after digestive histamine challenge (DHC) in patients with CU compared with controls. An abnormal increase in plasma histamine was observed in 72% of them. Plasma MH exhibited the same kinetic behaviour with a usually delayed time-pattern. Urinary MH concentration was higher in patients presenting with early-onset urticaria during the first hour than in those with the late-onset type between 1 and 12 hr after DHC. The coefficient of methylation (plasma MH/MH+H) was not significantly different in patients presenting with an attack of urticaria following DHC and in other subjects. Urinary excretion of MH and urinary flow increased significantly in patients presenting with an attack of urticaria following DHC which corresponds to increased absorption of histamine during the 5-hr period following DHC and its role on excretion by the kidney via vasodilation which it induces. This study demonstrates the abnormal frequency of disturbances in the metabolism of exogenous histamine in patients with CU. Increased plasma H accounts for the abnormal passage of H across the intestinal barrier which can result either from intestinal hyperpermeability and/or a deficit in the enzymatic catabolism of histamine. The systems of methylation and urinary clearance of MH appear to be effective. It is thus postulated that there is a deficit in diamine oxidase (DAO) in the enterocyte. The lack of correlation between the kinetic behaviour of plasma H and the onset of urticaria draws attention to the extent of individual variability in skin reactivity to histamine.