Prostate cancer (PCa) is a major health issue in Westernized countries, representing a common cause of morbidity and mortality in the elderly male population. Endogenous sex steroids, along with environmental factors (notably diet) and host immune and inflammatory responses, are likely to cooperate in the pathogenesis of the disease. Based on the assumption that a complex endocrine–inflammatory-immune interaction is primarily implicated in human PCa, we have investigated the interplay between sex steroids and inflammation in development and growth of human PCa. To this end, we have assessed nine functional single nucleotide polymorphisms (SNP)s of five genes involved in sex hormone-related pathways in both hyperplastic and malignant human prostate tissues, as well as in matched controls and in a ‘‘supercontrol’’ group composed of male Sicilian centenarians. In particular, the following genes were investigated: AR-OMIM313700, SRD5A2-NM-000348, CYP19-NM-031226, ERS1-NM-001122742, ERS2-NM-001040276. A significant association with prostate cancer was found in seven out of the nine SNPs considered. Although this is a preliminary study and larger investigations are needed to confirm the role of these genes in PCa development and/or progression, our data might provide an experimental basis to develop additional or alternative strategies for prevention and treatment of PCa.