The pathogenesis of Hirschsprung's disease (HD) is not fully understood. The authors studied expression of intercellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) class II antigen in the resected bowel specimens of 18 patients with HD who had no evidence of enterocolitis and in eight age- and site-matched controls, using indirect immunohistochemistry. There was strong expression of ICAM-1 and MHC class II antigen on hypertrophic nerve trunks, in both the submucous and myenteric plexuses of the aganglionic colon. The transition zone showed strong expression of ICAM-1 and MHC class II antigen on small ganglia in the myenteric and submucous plexuses. However, no staining of ganglia or nerve fibers was found in the submucous and myenteric plexuses of the colon from controls or in the ganglionic colon from patients with HD. The expression of both antigens on hypertrophic nerve trunks suggests the presence of an immunologic response in the pathogenesis of HD.