Although injection of cholecystokinin can reduce resting lower esophageal sphincter pressure, the physiological significance of this finding has not been established. The purpose of this double-blind crossover study was to determine the effect of physiological plasma levels of cholecystokinin on resting lower esophageal sphincter pressure. Eighteen normal male volunteers were studied on two separate days. Following a 20-minute baseline period, subjects received infusions of saline or synthetic cholecystokinin-8 at increasing rates. Basal plasma cholecystokinin levels averaged 1.3 +/- 0.2 pmol/L (mean +/- SE) and increased to levels of 7.4 +/- 0.9 pmol/L, 12.1 +/- 2.4 pmol/L, and 23.1 +/- 3.8 pmol/L during cholecystokinin infusion rates of 21, 42, and 84 pmol/min, respectively. Lower esophageal sphincter pressure was recorded continuously with a sleeved catheter. Basal lower esophageal sphincter pressure averaged 19.9 mm Hg and did not change with the first infusion, which produced physiological peak postprandial plasma levels of cholecystokinin. Lower esophageal sphincter pressure declined only during the infusions that produced plasma cholecystokinin levels two to four times greater than normal peak postprandial levels. Since infusion of cholecystokinin to levels that reproduce physiological blood levels does not significantly decrease lower esophageal sphincter pressure, it was concluded that cholecystokinin is not a major hormonal regulator of lower esophageal sphincter relaxation.