Adenocarcinoma of the female urethra accounts for 10% of all urethral cancers. Controversy continues to exist over the origin of primary urethral adenocarcinomas. The periurethral (Skene's) glands appear to be the homologues of the male prostate as defined by authors evaluating cadaver-derived periurethral glands pathologically and immunohistochemically (prostate-specific antigen (PSA)). It is traditionally assumed that the origin of female urethral adenocarcinoma is the Skene's gland. However, no one has evaluated a series of primary urethral adenocarcinomas in an effort to scrutinize this assumption. We, therefore, evaluated 13 primary adenocarcinomas of the female urethra comparing histologic and immunohistochemical characteristics. Tumors were classified into two major histologic groups: columnar/mucinous (11) and clear cell (2). Excluding one case, the columnar/mucinous tumors resembled either endometrial or colonic adenocarcinoma. The exception was a case bearing a striking resemblance to prostatic adenocarcinoma. Immunohistochemical results revealed positive PSA staining for this tumor alone. The patient's preoperative serum PSA was elevated, but rapidly declined postoperatively. Based on immunohistochemical findings and the presence of distinct histologic subtypes (columnar/mucinous, clear cell), it appears that female urethral adenocarcinoma has more than one tissue of origin with a minority arising from the Skene's glands.