Angiomyofibroblastoma (AMFB) of the genital region is a relatively recently described tumor of the superficial soft tissues with a marked preference for female patients. Three cases of AMFB were reviewed, two of which involved adult men. To further elucidate the pathologic features of AMFB, these three cases were compared with 10 cases of aggressive angiomyxoma (AA), a salient diagnostic alternative, and 28 cases of other myxoid tumors that may show morphologic similarities to these neoplasms. Conventional histologic and immunohistochemical features of AMFBs were compared with those of AA, myxoid leiomyoma, myxoid leiomyosarcoma, myxoid liposarcoma, myxoid malignant fibrous histiocytoma, myxoid neurofibroma, and myxoid malignant peripheral nerve sheath tumor. The ultrastructure of two of the three AMFBs also was analyzed.Genital AMFBs were circumscribed, partially myxoid proliferations that demonstrated considerable variation in cellular density. Neoplastic elements were bland cytologically and showed both fusiform and epithelioid profiles, with a tendency to concentrate around intralesional blood vessels. Mitotic activity and necrosis were absent, and the vessels assumed an arborizing configuration and were venule or capillary sized. In contrast, all other tumor types evaluated were infiltrative, cytologically atypical, or both. All AMFBs showed immunoreactivity for vimentin, desmin, actin, and estrogen receptor protein. These results were shared by most examples of AA and smooth muscle tumors as well, but were not seen in any other neoplasms in this study. Electron microscopic findings in cases of AMFB supported the presence of myofibroblastic differentiation in the tumor cells. These results indicate that conventional morphologic analysis is paramount in the recognition of genital AMFB but that immunohistology may be helpful in a limited context in excluding other differential diagnoses. They also support the conclusion that AMFB, AA, and superficial smooth muscle tumors have similar morphotypes and immunohistologic attributes regardless of their origin in men or women. Angiomyofibroblastoma (AMFB) is a recently described tumor that involves the vulvar soft tissue of young to middle-aged women. Fewer than 40 cases have been reported. [1][2][3][4][5][6][7][8] The importance of this entity is related to its potential mimicry of a more infiltrative and prognostically less favorable lesion found in the same anatomic area, namely, aggressive angiomyxoma.9 " 22 To a lesser extent, AMFB is capable of simulating the histologic features of other myxoid superficial soft tissue tumors as well. In an addendum to the seminal paper on this neoplasm, Fletcher et al 1 briefly chronicled a single case of AMFB that developed in the scrotum of a 66-year-old man. We describe three additional cases of AMFB in the inguinoscrotal region in two men (ages 62 and 63 years, respectively) and the vagina in a 50-year-old woman, and formally compare the immunohistologic features of these lesions with those of other myxoid neoplasms includ...