The effects of calcium and secretin were studied in 8 patients with the Zollinger-Ellison syndrome and 18 patients with duodenal ulcer disease. Intravenous infusion of calcium gluconate produced marked increases in serum gastrin levels in the patients with Zollinger-Ellison syndrome (4,350 +/- 1,625 pg/mg) and very slight increases in the patients with duodenal ulcer disease (140 +/- 49 pg/ml). Secretin given as a single intravenous injection also induced marked elevations in serum gastrin in the group with the Zollinger-Ellison syndrome (4,063 +/- 1,990 pg/ml). By contrast, intravenous secretin resulted in a progressive fall in serum gastrin levels in the duodenal ulcer group (from 119 to 97 pg/mg). These results suggest that both stimuli are very useful dagnostic tools in discriminating between Zollinger-Ellison and non-Zollinger-Ellison patients. The secretin challenge test is felt to be superior to the calcium infusions because it is simpler, safer and very rarely produces false-negative or-positive results.