Abstract There is an urgent need for reliable markers to identify patients whose PCa is most likely to recur after initial therapy and progress to lethal disease. While Gleason score is considered the most accurate predictive marker for disease-specific mortality after primary treatment of localized prostate cancer (PCa), the majority of PCas cluster into intermediate group of Gleason scores 6 and 7 where there is considerable variation in treatment response, disease recurrence and disease-specific death. In this study, we analyzed the predictive value of elevated nuclear Stat5a/b expression in PCas treated by radical prostatectomy or active surveillance. The critical role of Stat5a/b in promotion of PCa growth and progression has been well-documented in preclinical PCa models. Specifically, Stat5a/b is critical for prostate cancer cell viability in vitro and for prostate tumor growth in vivo, and Stat5a/b promotes metastatic dissemination of prostate cancer in nude mice. Here, we demonstrate that in intermediate Gleason score PCas treated by radical prostatectomy, high levels of nuclear Stat5a/b predicted both early recurrence (univariate analysis; p<0.0001, multivariate analysis; HR=0.55, p=0.017) and early PCa-specific death (univariate analysis; p=0.028). In addition, high nuclear Stat5a/b predicted early disease recurrence in both univariate (p<0.0001) and multivariate (HR=0.62; p<0.01) analysis in the entire cohort of patients treated by radical prostatectomy (n=562) regardless of the Gleason score. In the second group of patients treated by active surveillance, elevated nuclear Stat5a/b expression was associated with early PCa-specific death (p=0.0453) by univariate analysis (Cox regression analysis: 60% increased risk of death, p=0.034). If confirmed in future prospective studies, nuclear Stat5a/b may become a useful independent predictive marker of recurrence of lethal PCa after radical prostatectomy for intermediate Gleason score PCas. Citation Format: Tuomas Mirtti, Benjamin E. Leiby, Pär Stattin, Anders Bergh, Marja T. Nevalainen, Junaid Abdulghani, Miia Pavela, Elina Aaltonen, Anita Mamtani, Kalle A. Alanen, Lars Egevad, Torvald Granfors, Andreas Josefsson. Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C41.