To clarify the pathogenesis of oral plague infection, we studied the susceptibility of three species of rodents to intragastric inoculation of Yersinia pestis, described the pathology and progression of infection, and measured antibody responses to fraction IA antigen of Y. pestis. The 50% lethal doses of bacteria by intragastric inoculation for Mus musculus, Zygodontomys pixuna, and Rattus rattus were log10 = 6.32, 5.46, and 9.62, respectively, which were at least 1,000-fold higher than the values obtained by subcutaneous inoculation. M. musculus was shown to be susceptible to lethal infection also when bacteria were ingested in drinking water. Microscopic pathology was consistent with heavy systemic infection. Quantitative cultures of tissues at different times after intragastric inoculation revealed that infections of blood, liver, and spleen preceded infections of Peyer's patches and mesenteric lymph nodes. Stool cultures were negative. The strain of Y. pestis used for inoculation was killed when exposed to a buffered solution at pH less than or equal to 3. Antibody responses were observed in some of the surviving rodents after intragastric challenge. These results showed that Y. pestis was an effective oral pathogen that produced fatal systemic infections and self-limited infections with immunity but did not produce enteric pathology or lead to fecal excretion of bacteria.