Immunodetection of the Lewis X antigen has been suggested as a useful adjunct in the diagnosis of transitional cell carcinoma. To determine the specificity of Lewis X antigen immunostaining in this setting, we studied routinely processed, formalin-fixed tissue from 38 transitional cell carcinomas and 42 nonneoplastic urothelial lesions using the P12 monoclonal antibody to Lewis X antigen and an avidin-biotin immunohistochemical technique. Because Lewis X immunostaining of occasional umbrella cells has previously been noted in normal urothelium, staining of umbrella cells was not considered sufficient for a positive reaction in our study. Immunoreactivity for Lewis X antigen was seen in 34 of 38 (89%) cases of transitional cell carcinoma, in three of three cases of urothelial dysplasia, and in 20 of 39 (51%) of the reactive urothelial lesions. We conclude that immunostaining for the Lewis X antigen is not specific in the diagnosis of transitional cell carcinoma.