Background: Two French families were investigated. In the first a husband, wife, and 4 children had Crohn's disease; in the second 7 of 11 children had the disease. There was no history of Crohn's disease in antecedent generations and no linkage to HLA haplotypes. Methods: Methods included family interviews; review of medical records, radiographs, and pathology slides; serology; selective stool culture; enzyme-linked immunosorbent assay for fecal viral detection; and immunocytochemistry. Results: In both families multiple cases occurred among siblings in 7-13-month periods. There appeared to be a 4-8-year recurrence of new disease in both families. Radiographs showed a remarkable similarity in the pattern of disease, confined to distal ileum and cecum, in the members of family 1. Examination for pathology showed granulomas in all 8 patients for whom tissues were available. Acid-fast organisms or Campylobacter-like organisms were not found in tissue sections, and immunocytochemistry was negative for mycobacteria and Yersinia. Stool cultures were negative for mycobacteria, Yersinia, and Mycoplasma. Torovirus and coronavirus antigens were not found in stool. Serology was negative for antibodies to Brucella, Yersinia, influenza, and three enteropathogenic viruses of animals. Conclusions: The circumstances and data suggest that an infectious microorganism is responsible for these clusterings of Crohn's disease.