Autoimmunity has been emphasized in the pathogenesis of ulcerative colitis and various anticolon antibodies have been described. Nevertheless, the nature of the autoantigens has been elusive. Using ulcerative colitis colon-eluted IgG antibody, we earlier detected an M(r) 40,000 protein, P40, in colon extract. In our study, we purified P40 from human colon to apparent homogeneity, sequenced two peptides after proteolytic digestion, and demonstrated that the P40 belongs to the tropomyosin family. Furthermore, we demonstrated that blood serum from 95% of patients with ulcerative colitis contains antibodies that are reactive to tropomyosin.