Abstract Background: Akt is an ubiquitous signaling molecule that is associated with a wide array of biological effects including cell growth and proliferation. The dysregulation of Akt has been associated with cancer cell transformation, invasion and metastasis. While the roles of mutations in FGFR3, p53 and Ras have been the focus of the majority of studies of Transitional cell carcinoma (TCC) of the bladder, recent evidence suggests a link between the Akt pathway and the progression of TCC. Mutations in Akt pathway members have been identified in subsets of bladder TCCs, and Akt activation in TCC cell lines confers resistance to chemotherapeutics and promotes invasion in vitro. This led us to hypothesize that activated Akt may be an important biomarker in the progression of muscle invasive TCC. Methods: Tissue was obtained from 67 patients who had undergone radical cystectomy procedures for treatment of muscle invasive TCC. Tissue sections were taken from paraffin embedded samples and subjected to immunohistochemical analysis with anti Akt antibody to detect the activated form of Akt. A database of patient demographics, disease, treatment and survival parameters was generated and used to correlate 4, 12, 24 and 36 month disease-free intervals (DFI). Results: 53 of the 67 patients had sufficient follow-up to allow for DFI analysis. Of these 53 patients, 48 stained positively for pAkt, while 5 stained negatively. None of the pAkt negative patients had recurrent disease, while the pAkt negative patients suffered cumulative recurrence in 10, 19, 24, and 25 of the 48 patients at 4, 12, 24 and 36 months respectively. Chi square analysis reveals statistically significant differences in recurrence rates between pAkt negative and negative patients at 24 (p=0.0235) and 36 months (p=0.016). Tumor stage and nodal status were also strong predictors of recurrence. Conclusions: pAkt negative patients were found to have a significantly better prognosis for TCC recurrence, which indicates that pAkt status could be useful in helping to determine the prognosis for patients with muscle invasive TCC. These results lead us to speculate that the use of a serine threonine kinase inhibitor may prove to be therapeutically beneficial for TCC patients undergoing concurrent chemotherapy for their disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4187. doi:10.1158/1538-7445.AM2011-4187