Neuroendocrine differentiation of prostatic adenocarcinoma has received considerable attention in recent years. The objectives of this study were to characterize the incidence, pattern of distribution and peptide hormone immunoreactivities of neuroendocrine differentiated tumor cells in prostatic carcinoma metastases; determine the correlation of neuroendocrine differentiation and deoxyribonucleic acid content in lymph node metastases, and determine the prognostic role of neuroendocrine differentiation of metastases in stage D1 cancer. We examined immunohistochemically 62 metastatic lesions (41 pelvic lymph nodes and 21 bone metastases) for the presence of chromogranin-A expressing tumor cells. Of 41 lymph nodes and 21 bone metastases 19 (46%) and 11 (52%), respectively, contained chromogranin-A immunoreactive cells. These cells were commonly found to comprise the minority of tumor cells in the metastases and typically were distributed in a dispersed pattern. Serotonin and peptide hormone immunocytochemistry in 19 cases (12 lymph nodes and 7 bone metastases) demonstrated neuroendocrine cells containing thyroid-stimulating hormone and serotonin in 17 (89%) and 10 (53%), respectively. All 7 bone metastases contained thyroid-stimulating hormone immunoreactive cells. The presence of chromogranin-A positive cells did not correlate statistically with deoxyribonucleic acid content of lymph node metastases nor with disease specific survival in patients with stage D1 prostate cancer. Our results indicate that a substantial proportion of prostate cancer metastases contain a subpopulation of cells expressing a neuroendocrine phenotype similar to primary tumors. These cells are capable of elaborating certain biogenic amines and peptide hormones. However, in stage D1 prostate cancer nodal lesions expressing neuroendocrine differentiation do not appear to have significant prognostic value.