Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Orebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions.