Abstract Recent epidemiological evidence suggests that Listeria monocytogenes (LM) is a food-borne pathogen in humans. A model of LM infection was developed using the Sprague-Dawley (SD) rat to study the interaction of LM with gastrointestinal epithelium as the first step in the pathogenesis of invasive listeriosis. Conventionally raised, juvenile female SD rats were given 10 2−10 9 virulent L. monocytogenes, serotype 4b or nonpathogenic Listeria species. Only rats given virulent LM developed dose-dependent invasive infection of the liver and spleen. Light and electron microscopic studies suggested attachment to and invasion of the gastrointestinal mucosa by virulent LM. Because the development of invasive listeriosis in humans has been epidemiologically associated with a decrease in gastric acidity, the effect of decreasing gastric acidity on dose-dependent infection was studied. Rats were pretreated with cimetidine (50 mg/kg) by intraperitoneal injection prior to oral inoculation of 10 2−10 9 virulent L. monocytogenes. Cimetidine significantly lowered the infective dose of virulent L. monocytogenes ( P<0.05). This oral model should allow further study of host and organism-specific virulence factors mediating the gastrointestinal phase of invasive LM infection, an increasingly important public health problem.