Chlordiazepoxide and clidinium each, as a function of dose, prevent stress-induced gastric mucosal erosion in mice. Clidinium was 2.5 times more potent than chlordiazepoxide. When used in a combination of 2 parts chlordiazepoxide and 1 part clidinium, the protective effect was nearly five times greater than that produced by clidinium alone. Furthermore, the combination dosing proved nearly three times more potent than the potency that was predicted from simple additivity of the individual drug effects. This potentiation appears related to the number of ways in which the combination treatment can decrease autonomic input to the gastric mucosa. Thus, the peripheral cholinergic blockade by clidinium may be potentiated by a central chlordiazepoxide suppression of both sympathetic and parasympathetic activities. Therefore, the combined use of these drugs in the therapy of stress-induced gastric disorder appears to have a rational pharmacologic basis.