EpCAM is comprised of an extracellular domain with epidermal growth factor and thyroglobulin repeat-like domains, a single transmembrane domain, and a short 26-amino acid intracellular domain called Ep-ICD. In normal cells, this full length EpCAM protein is sequestered in tight junctions and therefore less accessible to antibodies, whereas in cancer cells it is homogeneously distributed on the cancer cell surface and has been explored as a surface-binding site for therapeutic antibodies. EpCAM is expressed in majority of human epithelial cancers, including breast, colon, gastric, head and neck, prostate, pancreas, ovarian and lung cancer and is one of the most widely investigated protein for its diagnostic and therapeutic potential. Increased EpCAM expression is a poor prognostic marker in breast and gall bladder cancers, while it is associated with favorable prognosis in colorectal and gastric cancers. This paradoxical association of EpCAM expression with prognosis in different cancers may be explained by the functional studies of EpCAM biology using in vitro and in vivo cancer models. Taken together these studies suggest that the impact of EpCAM expression in human cancers is likely to be context-dependent. EpCAM expression based assay is the only FDA-approved test widely used to detect circulating tumor cells in breast cancer. Trichostatin A EpCAM-targeted molecular therapies are being intensely pursued for several cancers including breast, ovarian, gastric and lung cancer. EpCAM expression has been used to predict response to anti-EpCAM antibodies in breast cancer patients. Surprisingly, clinical trials of anti-EpCAM antibodies targeting the EpEx domain have shown limited efficacy in cancer therapy and its negative prognostic potential for survival of cancer patients remains unclear. This might be explained by the recently unraveled mode of activation of EpCAM oncogenic signaling by proteolysis and the potential of Ep-ICD in triggering more aggressive oncogenesis. Regulated intra-membrane proteolysis of EpCAM results in shedding of EpEx and release of Ep-ICD into the cytoplasm, nuclear translocation and activation of oncogenic signaling. Previously, we reported accumulation of Ep-ICD is frequently detected in ten epithelial cancers, including breast and prostate; in thyroid carcinomas nuclear Ep-ICD accumulation predicted poor prognosis. The aim of this study was to evaluate the prognostic utility of Ep-CAM by characterizing the subcellular expression of Ep-ICD and membranous expression of EpEx in PCa using immunohistochemistry and correlating with clinic-pathological parameters and the follow up of patients. This would help investigate its potential to predict aggressive tumors that may aid in better management of patients. Prostate cancer management has come a long way in helping patients overcome cancer recurrence. In this study we have provided evidence that PCa patients having an increase in nuclear Ep-ICD and membranous EpEx were found to have better survival.