A simple animal model was used to demonstrate passive protection by immunoglobulin A (IgA) against a mucosal pathogen, Vibrio cholerae. Oral administration of a monoclonal IgA directed against a lipopolysaccharide component of the vibrio protected neonatal mice against oral challenge, as measured by reduced intestinal colonization. A single dose of 0.1 microgram of polymeric monoclonal IgA given 1 h prior to challenge reduced the number of recoverable vibrios by at least 100-fold. An additional dose 3 h before challenge or 1 h after challenge did not enhance protection. A 10-fold-higher concentration of monomeric IgA was required to achieve the same level of protection as that conferred by polymeric IgA. Polymeric IgA digested with trypsin or human duodenal aspirates to lower-molecular-weight fragments retained most of its ability to protect mice against challenge.