The objective of this study was to present two cases of adenosquamous cell carcinoma of the prostate following radiation therapy. Two patients with history of prostate cancer treated with radiation therapy presented with rectal bleeding and a large ulcerated rectal mass. The rectal biopsy revealed on both cases squamous cell carcinoma. The initial diagnosis was invasive squamous cell carcinoma from anal origin. Both patients underwent pelvic exenteration with continent urinary diversion. After extensive histological sampling and immuno-histochemisty, they were correctly diagnosed of adenosquamous cell carcinoma of the prostate with invasion of the rectum. The patients died 6 and 16 months after surgery with widespread metastases. A review of the literature is presented. Adenosquamous cell carcinoma of the prostate is an unusual histological variant of prostate cancer. To our knowledge, only three cases of adenosquamous cell carcinoma of the prostate following radiation therapy have been reported. The unusual clinical and histopathological features of the two cases reported here led to an initial mistaken diagnosis. Adenosquamous cell carcinoma of the prostate should be considered in the differential diagnosis when a patient with prostate cancer develops a rectal mass or rectal bleeding following radiation therapy and the rectal biopsy reveals squamous cell carcinoma. Prostate Cancer and Prostatic Diseases (2000) 3, 53-56