Duodenal ulcers can be produced in rats by subcutaneous administration of cysteamine-HCl. The pathogenesis of these ulcers has not been fully explained. Increased acid secretion is necessary but not sufficient for ulcer production. In the present study we have observed pronounced alterations in the histologic appearance of the duodenal glands of Brunner during ulcer formation. The secretory cells became extremely flattened without mucus content and the lumina of the acini dilated. Changes became most pronounced between 4 and 8 h after administration of cysteamine. Repeated injections of pentagastrin in a dosage inducing an acid response equivalent to the one induced by cysteamine did not produce any histologic changes in Brunner's glands or any ulcerations. When cysteamine was administered to rats with chronic gastric fistulas draining the gastric secretions, no duodenal ulcerations were produced, but Brunner's glands still became depleted of mucus. These findings suggest that the histologic changes in Brunner's glands are not secondary either to the increased acid secretion induced by cysteamine or to ulcer formation. Together with our previous demonstration of a marked reduction duodenal secretion in the first 10 h after cysteamine administration, the results of the present study suggest an inhibitory effect of cysteamine on the synthetic activity of Brunner's glands rather than an impaired release mechanism. The effect of cysteamine on Brunner's glands may be an important factor in the pathogenesis of cysteamine-induced duodenal ulceration.