Prostate cancer is the most common cancer in North American men. Currently available prognostic factors inadequately predict which cancers will be aggressive and which will lead an indolent course. This study was aimed at investigating the role of matrix metalloproteinase (MMP)-2 in prostate cancer disease-free survival. We correlated MMP-2 expression by malignant prostatic epithelium and stromal cells with prostate cancer disease-free survival in 187 stage pT3NxM0 prostate carcinomas using immunohistochemistry. MMP-2 was expressed by cancer cells in 131 cases (70.0%) and by stromal cells in 142 cases (75.9%). MMP-2 expression by stromal cells was not associated with progression (P = 0.7270). However, in multivariate analyses, adjusting for the Gleason score, tumor-node-metastasis stage, and initial serum prostate-specific antigen, MMP-2 expression by >50% of malignant epithelial cells was associated with decreased disease-free survival (hazard ratio, 4.267; P = 0.0012). Increased MMP-2 expression by malignant prostatic epithelia is an independent predictor of decreased prostate cancer disease-free survival.