Epithelial cell adhesion molecule (EPCAM) has recently attained a renewed interest as a candidate protein in diagnosis, prognostication and therapy of various tumor entities. The molecular epidemiology and prognostic relevance of EPCAM in renal cell carcinoma (RCC) and amongst the histological subtypes of RCC is unclear. We analyzed the prevalence and prognostic significance of EPCAM in a tumor tissue micro-array (TMA) composed of 1088 independent RCCs samples by immunohistochemistry (IHC). We found significant variations of EPCAM IHC staining intensities in between the RCC subtypes: In papillary and chromophobe RCC, the majority of tumors (89-93%) showed an at least weak EPCAM protein expression. In the largest subgroup, the clear cell (cc)RCC (n=767), a negative EPCAM IHC was found in 1/3 of the patients and was associated with high-grade disease and nodal metastases. Kaplan-Meier analyses demonstrated a significant association between positive EPCAM IHC and prolonged overall survival, even in a subset of low risk ccRCC. In multivariable analyses, EPCAM represented an independent risk factor of survival throughout all subgroups. For localized, low-grade ccRCC, information of EPCAM IHC raised predictive accuracy of a multivariate model by ∼5%, compared to T-stage and grade alone. Our findings indicate, that EPCAM is an independent prognostic molecular marker in ccRCC and, especially in localized ccRCC, might be able to provide auxiliary information for a better prognostication.