A variety of bacterial pathogens including Campylobacter, Yersinia, Listeria, Brucella, and Mycobacteria have been suggested as potential etiologic agents for Crohn's disease. To assess the role of these organisms we studied responses to eight antigens in sera from patients with active Crohn's disease and healthy age- and sex-matched controls. In complement-fixation assays, the sera from the Crohn's disease patients had enhanced reactivity compared with the control sera to all seven orally ingested pathogens studied; however, only the difference in distribution of titers to Yersinia pseudotuberculosis was statistically significant (p less than 0.0025). There was no difference between the two groups in reactivity to arabinomannan, a common mycobacterial antigen. Seroreactivity to enteric pathogens not resident in the bowel flora probably represents a nonspecific sensitization to cross-reacting antigens. Lack of response to the mycobacterial antigen suggests that widespread mycobacterial disease with high bacillary load is not present in Crohn's disease.