Smoking is associated with an increased incidence of duodenal ulcer with a high relapse rate, and smokers tend to be slow healers. The etiology responsible for this remains unknown, and there is general disagreement as to whether smoking affects gastric secretion. The aim of the present study was to investigate both aggressive and protective factors in response to vagal stimulation induced by modified sham feeding (MSF) in duodenal ulcer patients when smoking versus not smoking. On smoking days, nicotine concentrations in plasma averaged about 15 ng/ml and were extremely high in saliva and gastric juice (>1300 and >800 ng/ml, respectively). MSF induced a significant decrease in intragastric pH during non-smoking (p = 0.01) but not during smoking. Acid output 1 h after MSF was lower on smoking than on non-smoking days (p = 0.02), as was volume secretion (p = 0.02). Plasma gastrin concentrations were significantly increased during MSF on non-smoking days (p = 0.04) but not on smoking days, the concentrations during the whole day being lower on smoking days (p = 0.002). Plasma catecholamine levels were unaffected by MSF, whether smoking or not. However, plasma concentrations of noradrenaline decreased during the smoking of a single cigarette (p = 0.03), whereas those of adrenaline were increased on smoking days (p = 0.02). Epidermal growth factor concentrations were decreased in gastric juice after MSF during non-smoking (p = 0.01) but not during smoking. Although prostaglandin E₂ (PGE₂) concentrations in gastric juice were unaffected by MSF, PGE₂ output increased after MSF whether smoking or not, the increment being non-significantly less during smoking (p = 0.09). Neither MSF nor smoking seemed to affect bile reflux. The results of this study indicate that factors other than stimulated gastric acid secretion are responsible for the increased ulcer susceptibility in smokers. Possibly, the very high nicotine concentrations in gastric juice affect the cytoprotective properties of the mucosa and may even have a direct toxic effect on the epithelial cells.