Primary epididymal carcinoma is extremely rare and has been the subject of only sporadic case reports; the validity of some of the reported tumors is questionable. We report our experience with four examples, which arose in men 27, 66, 77, and 81 years of age. All of them presented with scrotal masses; three of them had small hydroceles. None had a history of von Hippel-Lindau disease. Grossly, all of the tumors were centered in the epididymis and two were confined to it. One tumor invaded the periepididymal soft tissue and spermatic cord and the fourth invaded the adjacent testis. They were 2.0-7.0 cm in greatest diameter; three had foci of hemorrhage and necrosis. Microscopically, all of the tumors were adenocarcinomas. Two of them were composed of approximately equal numbers of simple tubules and more complex tubulopapillary formations lined by cuboidal or columnar predominantly clear cells that infiltrated the epididymal smooth muscle wall, periepididymal soft tissue, or both. The other two had large cysts into which grew complex papillary or confluent, back-to-back glands lined by columnar cells with clear, lightly amphophilic or eosinophilic cytoplasm. Necrosis was present in three cases. An undifferentiated, sheetlike growth of anaplastic tumor cells was present focally in one case. Cilia were absent. Small amounts of cytoplasmic glycogen were present in the two cases in which periodic acid-Schiff staining was performed. Immunohistochemical staining, performed in one case, demonstrated strong positivity for cytokeratins (AE1/3, Cam 5.2) and epithelial membrane antigen (luminal only). Results of staining for carcinoembryonic antigen, Leu M1, B72.3, and Ber-EP4 were negative. Ultrastructural analysis, performed in one case, showed well-developed desmosomal junctions, cytoplasmic multivesicular bodies, glycogen particles, and well-developed cilia. Two of three patients with follow-up data died of disease 8 months and 2.5 years after diagnosis; the third was disease free 30 years after the diagnosis despite having paraaortic lymph node metastases at the time of presentation. After reviewing the literature and analyzing our cases, we conclude that bona fide examples of epididymal adenocarcinoma are usually tubular, tubulocystic, or tubulopapillary adenocarcinomas, often with an appreciable content of clear cells, which can usually be readily separated from other paratesticular malignant tumors, such as malignant mesothelioma and carcinomas of the müllerian type. Distinction from metastasis may be difficult and may depend largely on careful clinical evaluation.