The epithelial destruction seen in ulcerative colitis remains unexplained. Complement activation has been proposed to be involved, but no definite evidence has been available to this end. In the present study, we examined immunohistochemically ulcerative colitis lesions with monoclonal antibodies to activation neoepitopes in the complement component C3b and in the cytolytically active terminal complement complex. Colonic tissue specimens from 23 patients with ulcerative colitis were examined by indirect two-color immunofluorescence staining with monoclonal antibodies to the four human immunoglobulin G subclasses and to activated complement C3b or terminal complement complex. All except two patients had activated C3b deposited apically on the surface epithelium of involved mucosa. Immunoglobulin G1 was found on the epithelium in extensively prewashed specimens from 7 of 11 patients, and a striking colocalization of immunoglobulin G1, C3b, and terminal complement complex was observed in 4. Immune deposits were not observed in 31 noninflamed specimens from the same ulcerative colitis patients. Only 1 of 44 histologically normal mucosae from 17 controls and 1 of 10 colonic adenomas contained some epithelial complement deposits. It is concluded that activated complement is often deposited along the brush border of the surface epithelium in active ulcerative colitis lesions and may be associated with immunoglobulin G1 autoantibody.