The effect of smoking one unfiltered cigarette every 15 min for 1 hr on basal gastric acid and pancreatic secretion was studied in 10 subjects with a history of duodenal ulcer and 10 without duodenal ulcer. Smoking induced a transient rise of basal acid output followed by a slight decrease. This effect was more pronounced in the duodenal ulcer group. Smoking markedly inhibited fluid and bicarbonate secretion during the smoking period. The bicarbonate and fluid secretion returned to control levels within 30 to 60 min in the ulcer group and in 60 to 90 min in the nonulcer group. There was no difference in the degree of inhibition of pancreatic secretion between the two groups. Immunoreactive gastrin and secretin in the peripheral venous blood did not change significantly during smoking. The degree of inhibition of basal pancreatic secretion correlated well with the plasma concentrations of nicotine. These observations indicate that smoking in the fasting state induces alterations of basal gastric and pancreatic secretions which are not related to changes in plasma gastrin and secretin concentration, but to plasma concentrations of nicotine. The implication of this study in relation to a possible causal association between cigarette smoking and peptic ulcer disease is discussed.