The IgA response of gut associated lymphoid tissue (GALT) to enteric pathogens is a vital component of the mucosal barrier. This study describes the effect of cyclophosphamide (Cy) on the IgA anti-CT response of Peyer's patch (PP) and lamina propria cells derived from mice previously challenged enterically with two weekly doses of 10 micrograms CT. Under normal circumstances, both PP and lamina propria responses peaked 7 days after the second dose of CT. To evaluate the effect of a single dose of Cy on this response, mice were given Cy (50 mg/kg) intravenously on days -2, 0, 2 or 7 relative to the initial dose of CT. Cultures of PP and jejunal segments were established 7 days after the booster dose of CT (time or normal peak response). A single dose of Cy suppressed the IgA anti-CT response of PP and, to a lesser extent, jejunal segment cultures only if the drug was given 2 days before the primary dose of CT. This suppression of the anti-CT response was overcome when Cy was given 2 days before CT priming, and CT was administered three times, on days 0, 7 and 14; thus, the effect of Cy was brief and did not appear to promote tolerance to CT. These data show that a single, moderate dose of Cy, given before enteric priming of the GALT, can inhibit the mucosal IgA response to CT. The effect of Cy is relatively brief and dependent upon the time at which the drug is given relative to the induction of the mucosal immune response.