The G-protein coupled receptors (GPCRs) recognize a large variety of extracellular molecules (such as hormones, neurotransmitters, growth and developmental factors) and several sensory messages (such as light, odors and pain). GPCRs and their signal transduction pathway represent important specific targets for a variety of human diseases. To investigate the potential roles of GPCRs in human normal prostate and prostate cancers, we identified and characterized a novel human G-protein coupled receptor, PSGR2, which is highly overexpressed in human prostate cancers. Although PSGR2 shares sequence homology with human olfactory G-protein coupled receptors, the expression of PSGR2 is highly restricted to human prostate tissue, and no expression was detected in 22 normal and 10 tumor tissues examined using Northern blot and PCR analysis. Furthermore, we investigated the expression levels of PSGR2 in 133 human prostate samples with real-time quantitative reverse transcription-PCR and in situ hybridization method. We demonstrated that PSGR2 expression increased significantly in human high grade prostate intraepithelial neoplasia (PIN) and prostate cancers (approximately 10-fold) as compared to normal and BPH (benign prostatic hyperplasia) tissues (p < 0.001), suggesting PSGR2 may play an important role in human prostate cancer development and progression. Together, our results suggest that PSGR2 is a novel prostate specific G-protein coupled receptor and may be useful as a tissue marker and molecular target for the early detection and treatment of human prostate cancers.