Mel‐18 is a member of the polycomb group (PcG) proteins, which are chromatin regulatory factors and play important roles in development and oncogenesis. This study was designed to investigate the clinical and prognostic significance of Mel‐18 in patients with prostate cancer. A total of 539 native Japanese subjects consisting of 393 prostate cancer patients and 146 controls were enrolled in this study. Mel‐18 genotyping was analyzed using a PCR‐RFLP method and an automated sequencer using the GENESCAN software. Immunohistochemistry revealed that Mel‐18 expression was diminished in high grade and high stage prostate cancers. Moreover, patients with positive Mel‐18 expression had significantly longer PSA recurrence‐free survival than patients negative for Mel‐18 expression (p = 0.038). A Mel‐18 1805A/G SNP was located in the 3' untranslated region and was predicted to alter the secondary structure of the mRNA. Mel‐18 mRNA expression of the 1805A allele was clearly higher than expression of the 1805G allele by allele specific quantitative RT‐PCR. In multivariate analysis, a homozygous G allele genotype and negative Mel‐18 expression were independent risk factors predicting high PSA recurrence after radical prostatectomy, with HRs of 2.757 (p = 0.022) and 2.271 (p = 0.045), respectively. Moreover, the G allele was also an independent predictor of poor cancer‐specific survival with an HR of 4.658 (p = 0.019) for patients with stage D2 prostate cancer. This is the first study to provide important evidence demonstrating that Mel‐18 is a tumor suppressor and possible therapeutic target, as well as a diagnostic marker for poor prognosis in prostate cancer patients. © 2009 UICC