Based on a lack of severe phenotype in human immunoglobulin A (IgA) deficiency syndromes, the role of IgA in controlling respiratory and gastrointestinal (GI) infections has not been clearly defined. C57BL/6 and BALB/c mice lacking IgA (IgA(-/-)) were developed and used to address this question. When exposed to a common GI virus, rotavirus, IgA(-/-) mice exhibited a substantial and significant delay in clearance of the initial infection compared with wild-type mice. IgA(-/-) mice excreted rotavirus in stool up to 3 weeks after the initial exposure compared with 10 days observed in wild-type mice. Importantly, IgA(-/-) mice failed to develop protective immunity against multiple repeat exposures to the virus. All IgA(-/-) mice excreted virus in the stool upon re-exposure to rotavirus, whereas wild-type mice were completely protected against re-infection. These findings clearly indicate a critical role for IgA in the establishment of immunity against a GI viral pathogen.