BACKGROUND: Neuroendocrine (NE) cells increase in high grade/stage prostate cancer (PC) and may contribute to androgen-independent cancer. Their immunohistochemical phenotype has not been studied in detail and conflicting results have been reported. METHODS: PC tissue was stained immunohistochemically for luminal secretory cell-associated cytokeratin, basal cell markers, ki-67, androgen receptor (AR), PSA, prostate acid phosphatase (PAP), and alpha-methylacyl coenzyme A racemase (AMACR). RESULTS: The NE cells are positive for AE1/AE3, Cam 5.2, and negative for basal cell markers. They are negative for AR, PSA, and Ki-67 but positive for PAP. The benign NE cells are negative for AMACR while the malignant NE cells are positive for AMACR. CONCLUSIONS: NE cells of PC constitute a unique subset of cancer cells, which have a unique immunohistochemical profile. They do not express AR, consistent with their resistance to hormonal therapy. They are post-mitotic cells but are malignant and part of the tumor.