Clostridium difficile is an established cause of antibiotic-associated diarrhea and pseudomembranous colitis in humans and domestic and laboratory animals. Diagnostic findings support a role for C. difficile in neonatal enteritis of pigs. A typical case will occur in a piglet 1–7 days of age, with diarrhea beginning soon after birth. Pathology includes moderate to severe mesocolonic edema, sometimes accompanied by hydrothorax and/or ascites, with scattered foci of suppuration in the colonic lamina propria and accumulation of neutrophils in the mesocolon. Exudation of neutrophils and fibrin into the lumen gives rise to socalled “volcano” lesions. Cultures of affected tissues commonly yield heavy growth of C. difficile, and toxin testing almost invariably reveals the presence of toxins A and B. Treatment with antimicrobials and use of probiotics has yielded mainly unsatisfactory results, but bacitracin methylene disalicylate may be useful for prevention. The lack of commercially available immunoprophylactic products may cause producers to turn to autogenous bacterin/toxoids, but their effectiveness is uncertain.