Neuroendocrine (NE) differentiation within the primary prostate tumor has been correlated with tumor progression and shortened patient survival. Serotonin (5-hydroxytryptamine, 5-HT), a known mitogen, is found in most neuroendocrine cells of the human prostate. We have previously found that human prostatic carcinoma cell lines, PC-3, DU-145 and LNCaP, display certain NE characteristics. In this study, we have examined the effects of several subtype-selective 5-HT receptor antagonists on the growth of the three lines. Of these, the 5-HT1A antagonist pindobind had the most marked antiproliferative effect in vitro. Pindobind also had marked growth-inhibitory effects on the aggressive PC-3 cell line in vivo, in athymic nude mice. Radioligand binding studies indicated the presence of 5-HT binding sites on all three cell lines. Our results suggest that 5-HT is involved in the growth of prostate tumor cells and may serve as a target for treatment.