The differential diagnosis of mucin-producing adenocarcinoma of the prostate includes conventional prostatic adenocarcinoma with mucin production, secondary adenocarcinoma usually of colorectal origin and, very rarely, urothelial-type adenocarcinoma arising from either the prostatic urethra or proximal ducts. Conventional prostatic adenocarcinoma with mucin production is readily identified by routine microscopy and immunohistochemistry. The distinction between secondary adenocarcinoma and urothelial-type adenocarcinoma, however, can present a significant diagnostic challenge. In addition, documented examples of the latter in the prostate are exceptionally rare. A transurethral resection of prostate specimen and prostatic needle biopsies from two patients showing urothelial-type adenocarcinoma of the prostate were identified in our consultation files. One of the patients subsequently underwent a radical prostatectomy. Both patients had negative gastrointestinal endoscopic workups. Transurethral resection of prostate material from two patients with clinically confirmed secondary adenocarcinoma of colonic origin involving the prostate and a prostatectomy specimen with mucinous conventional prostatic adenocarcinoma were also identified for comparison purposes. Formalin-fixed, paraffin-embedded sections were stained for prostate-specific antigen (PSA), prostatic acid phosphatase, carcinoembryonic antigen, cytokeratin 7, cytokeratin 20 and high molecular weight cytokeratin 34betaE12. The urothelial-type adenocarcinoma cases were diffusely positive for cytokeratin 7 and focally positive for 34betaE12 and cytokeratin 20, consistent with an origin from the urothelium of the prostatic urethra or proximal prostatic ducts. In contrast, the secondary adenocarcinoma of colonic origin cases were diffusely cytokeratin 20 positive and either negative or focally positive for cytokeratin 7 and negative for 34betaE12. The mucinous conventional prostatic adenocarcinoma was positive for PSA and prostatic acid phosphatase and negative for cytokeratin 7, cytokeratin 20 and 34betaE12. All tumors were positive for carcinoembryonic antigen.