Neuroendocrine cells are thought to have a regulatory role in prostatic epithelial growth and may be prognostically useful in prostatic adenocarcinoma. To determine the extent of neuroendocrine differentiation in high-grade prostatic intraepithelial neoplasia (PIN), a putative precursor of cancer, we studied the immunohistochemical expression of 10 markers in 26 radical prostatectomy specimens with PIN and adenocarcinoma. Expression was measured as mean percent of positive cases and positive high-power (x40) fields. The highest percentage of cases showed immunoreactivity for serotonin (73%, PIN; 54%, carcinoma), neuron-specific enolase (NSE) (67%, PIN; 46%, carcinoma), chromogranin (62%, PIN; 65%, carcinoma), and human chorionic gonadotropin (hCG) (30%, PIN; 22%, carcinoma); the remaining markers showed immunoreactivity in fewer than 5% of cases (somatostatin, calcitonin, corticotropin) or in no cases (thyrotropin, prolactin, and glucagon). At least one of the markers was present in 88% of cases of PIN and 92% of carcinoma. Non-neoplastic epithelial cells expressed serotonin, NSE, chromogranin, and hCG in every case, and the expression was significantly greater than in PIN and cancer. Stepwise regression analysis revealed the following positive correlations: chromogranin expression in PIN and patient age, NSE expression in cancer and number of lymph node metastases, and hCG expression in cancer and percentage of Gleason pattern 5; serotonin expression in PIN and cancer did not correlate with any of the clinical and pathologic factors. Neuroendocrine differentiation is downregulated in prostatic carcinogenesis, with intermediate levels of expression in PIN compared with normal cells and carcinoma.