Abstract Enterocolitis is the most common cause of significant morbidity and death in Hirschsprung's disease. Although most cases respond to nasogastric decompression, antibiotics, and colonic evacuation, some children have an unusually fulminant or protracted clinical course. Four cases are reported of pseudomembranous colitis (PMC) that developed 1 to 18 months (mean, 8 months) after definitive surgery for Hirschsprung's disease (Soave endorectal pull-though, 2; Duhamel procedure, 2). While all children presented with fever, abdominal distention, and diarrhea, indistinguishable from typical Hirschsprung's enterocolitis, the clinical course was fulminant in two cases, both of whom died of septic shock. Postmortem examination in both showed extensive colonic pseudomembranes despite identification of Clostridium difficile toxin and subsequent vancomycin therapy (initiated late in the clinical course). Two children in the series had protracted hospitalizations and eventually required diverting enterostomy despite recognition of C difficile toxin and treatment with enteral vancomycin, in one child necessitating multiple courses of antibiotic therapy. Awareness of the virulence of PMC associated with Hirschsprung's disease (even after definitive resection) should prompt submission of stool specimens from any child who presents with enterocolitis for both C difficile culture and toxin levels. On the basis of our experience it is our policy to initiate a prompt course of vancomycin by rectal lavage or nasogastric tube in all children with Hirschsprung's enterocolitis, pending culture results, in view of the significant morbidity and mortality exemplified by cases in this review.