Prostate cancer is a biologically heterogeneous disease with considerable variation in clinical aggressiveness. The behavior of prostate cancer can be considered a direct or indirect result of aberrant alterations of gene expression in prostate epithelial cells. Identification of the patterns of gene‐expression alterations that are related to the aggressiveness of prostate cancers will greatly assist the development of tools for early detection of prostate cancers with poor clinical outcome and identification of targets for future therapeutic intervention. To detect the patterns of gene‐expression alterations of prostate cancers, we performed a comprehensive gene‐expression analysis on 30 prostate tissues of various levels of invasiveness (ranging from those confined to the organ to distant metastases) and Gleason grades (combined scores 4–9), using the Affymetrix chip set Hu35k (A–D) and U95a. Following three sequential selection screens, we identified 84 largely novel genes and expressed sequence tag (EST) sequences whose expression levels were altered significantly in prostate cancer samples compared with control normal tissues. In addition, the expression levels of a group of 12 genes and EST sequences was found to be altered significantly in aggressive type of prostate cancers but not in organ‐confined prostate cancers. Cluster analysis using the 84‐gene list showed that the highly aggressive prostate cancers contained gene‐expression patterns that were distinct from organ‐confined prostate cancers. © 2002 Wiley‐Liss, Inc.