Renal cell carcinoma (RCC) is the most common type of kidney cancer and recent developments in the molecular biology of RCC have identified multiple pathways associated with the development of this cancer. This study aimed at analyzing the expression pattern of cytokeratin 18 (CK18) in RCC patients and its prognostic relevance. We quantified CK18 mRNA expression and protein using real-time reverse transcription quantitative polymerase chain reaction (RT-QPCR) and immunohistochemistry, respectively, in paired tumor and non-tumor samples from 42 patients. Our data indicate that CK18 mRNA and proteins levels increased with advanced stage and grade of the disease. Using primary (RCC5) and metastatic renal cell carcinoma (RCC5 met) cell lines, we demonstrated that CK18 expression was 5-fold higher in the metastatic as compared to the primary RCC cell line and correlated with a migratory phenotype characterized by a distinct elongated morphology as revealed by Phalloidin staining. In addition, RCC5 met cells displayed an increased capacity to attach to fibronectin and collagen which was lost following CK18 knock-down. Our data also indicate that the expression of CK18 was associated with increased Snail expression which correlated positively with advanced disease in RCC patients. The present findings suggest that CK18 may play an important role in the progression of RCC and it may be used as a new predictor for RCC.