To more clearly define the pathophysiology of Hirschsprung's-associated enterocolitis (HAEC), this study comprehensively evaluates the gastrointestinal tissue of a group of infants with clinical HAEC. A pathologic grading system that demonstrates a progressive sequence of histologic changes specific for HAEC is established. The grading system correlates closely with clinical enterocolitis and may prove to be a useful method for early detection of infants at risk for the development of clinical HAEC. A significant alteration of intestinal mucins with an increase in neutral mucins and a decrease in acidic-sulfomucins was identified in HAEC tissue specimens. Enterocyte-adherent organisms were present in 39% of HAEC tissue specimens. The pathogenesis of HAEC may result from an alteration in intestinal mucins that may allow for the subsequent adherence of enteropathogenic organisms to enterocytes. The enterocyte-adherent organisms have the potential to induce an enterocolitic process and may contribute to both the intestinal and systemic manifestations of HAEC.