Nephrogenic adenoma (NA) of the prostatic urethra with involvement of the prostate gland can mimic other small-gland proliferations of the prostate, particularly adenocarcinoma of the prostate. To further characterize this lesion and refine diagnostic criteria we retrospectively reviewed the clinicopathologic features and immunohistochemical findings of eight cases of NA involving the prostate gland seen at The University of Texas M.D. Anderson Cancer Center from 1987 to 1992. The patients' ages ranged from 44 to 76 years (average age, 65 years). Six patients had lower genitourinary tract operations. Follow-up information was available for six patients (follow-up period, 5 to 38 months); only one patient had clinical evidence of recurrence (5 months after surgery). The remaining patients were alive and well with no evidence of disease. Histologically, NA was characterized by a proliferation of small tubules lined by a single layer of cuboidal or flattened cells with clear or eosinophilic cytoplasm. The nuclei were round with fine chromatin and there was no mitotic activity. Nucleoli were generally small, but occasionally prominent. All NA extended into the prostatic parenchyma, raising the possibility that these lesions may represent prostatic small-gland proliferations, particularly prostate adenocarcinoma. However, all cases tested were negative for prostate-specific antigen and prostatic acid phosphatase. Our findings indicate that the histologic features and the use of prostate-specific antigen and prostatic acid phosphatase immunostains will help to distinguish NA of the urethra involving the prostate from other small-gland proliferations (eg, small-acinar adenocarcinoma of the prostate, clear cell adenocarcinoma of the urethra, sclerosing adenosis, atypical adenomatous hyperplasia, florid hyperplasia of mesonephric remnants, simple lobular atrophy, and incomplete basal cell hyperplasia).