Nephrogenic adenoma is a benign lesion composed of small glandular structures that develops along the urothelium with uncertain pathogenesis. Some investigators believe that nephrogenic adenoma develops by a metaplastic process in response to injury to the urothelium, while others believe that it arises from detached renal tubules. Nephrogenic adenoma may be present in the prostatic urethra and morphologically mimic prostatic adenocarcinoma. Alpha-methylacyl-coenzyme A racemase (AMACR), a recently identified prostate cancer marker, is typically negative in normal urothelium and prostatic glands, and positive in distal convoluted renal tubules in addition to prostatic adenocarcinomas. Therefore, evaluation of AMACR expression in nephrogenic adenoma will have significance in the pathologic diagnosis and in understanding pathogenesis of this lesion. We studied 38 nephrogenic adenomas by clinical, histologic, and immunohistochemical analyses for AMACR (P504S) and high molecular weight cytokeratin (34betaE12). Twenty-two of 38 nephrogenic adenomas (58%) demonstrated strong cytoplasmic positivity for AMACR, ranging from patchy, focal to diffuse staining. In addition, 16 of 26 (62%) nephrogenic adenomas were negative for 34betaE12. To our knowledge, this is one of the first report of a completely benign lesion, which can be found in the prostate, showing strong AMACR immunoreactivity. Our findings suggest using caution when interpreting positive AMACR immunostaining in prostatic specimens. These findings could be explained by possible renal tubular origin or renal differentiation, at least in a subset, of nephrogenic adenomas.