Somatostatin (SRIF) has been demonstrated to inhibit in vitro proliferation of normal and transformed cells via SRIF receptors (SSRs). Moreover, like other neuroendocrine molecules, SRIF and SSRs may play a significant role in the progression and neuroendocrine differentiation of human prostate cancer (PCa). However, conflicting results have been reported in the literature on SSR heterogeneity and specific cell localization in PCa. In the present study, using the human androgen-dependent PCa cell line LNCaP, we investigated: 1) SSR subtypes expression in different culture conditions (10% and 2% FBS); 2) the effects of SRIF and of new agonists on cell proliferation. LNCaP expressed sst1, sst2A, sst3, sst5, at gene (RT-PCR) and protein (Western blot) level. SSR level of expression was differentially regulated by the culture conditions: sst2A and sst5 expression was not modified by serum concentration, whereas sst1 and sst3 expression was inversely correlated to serum concentration. Dose-response studies were performed at 24 and 48 h with a dose range from 10−11 to 10−7 M. SRIF inhibited cell proliferation ([3H]thymidine incorporation) after 24 and 48 h at all doses. The sst1 (BIM-23926), sst2 (BIM-23120) and sst5 (BIM-23206) preferential compounds did not affected cell proliferation. Conversely, lanreotide, inhibited cell proliferation after both 24 and 48 h with a maximum effect at 10−11 M, whereas, the bispecific sst2/sst5-preferential ligand BIM-23244 inhibited cell proliferation after 24 h at the dose of 10−9 M. The bi-specific sst1/sst2-preferential ligand BIM-23704 inhibited LNCaP proliferation after 48 h treatment, (dose range 10−10 M to 10−11 M). SSR subtype expression in PCa can be actively regulated by culture conditions, suggesting that receptor profile in PCa may depend from the tumor microenvironment. Finally, LNCaP represents a useful model for studying SSR regulation in PCa, intracellular subtype-linked signalling, and validate new analogues with different receptor affinities in PCa treatment.