The effects of preoperative irradiation on the morphology of transitional cell carcinomas (TCCs) were evaluated by studying the pretreatment biopsy and radical cystectomy specimens from 35 patients. Twenty-six of these patients had received 2000 rad within the week preceding surgery, and nine patients had received no preoperative treatment. The frequency of bladders without residual TCC was 23% for irradiated and 22% for nonirradiated cases. Of the TCCs classified as papillary in the biopsy specimens and irradiated, 79% lacked a papillary component at cystectomy, but in no case was the invasive component eliminated or regression from muscle invasion to superficial TCC noticed. Flat carcinoma in situ (CIS) did not respond to irradiation. At cystectomy nuclear pleomorphism was greater than at biopsy in 60% of the irradiated TCCs, whereas all nonirradiated cases retained the same grade as at biopsy. In addition, irradiation induced squamous differentiation in neoplastic cells only, without affecting the nonneoplastic urothelium.