It is known that renal cell carcinoma (RCC) is responsible for 3% of all malignancies. In America, it is estimated that approximately 58,000 new cases were diagnosed and 13,000 patients died from RCC in 2010 (1). It is the seventh most common malignancy in men and the ninth most common in women, and occurs predominantly in the sixth and seventh decades of life (1).Despite recent advances in the diagnosis and treatment of RCC, it is still a tumor of unpredictable presentation and clinical outcome. Currently, the only potentially curative treatment is surgery, through either radical nephrectomy or nephron sparing procedures. Systemic therapies such as anti-angiogenic agents show mixed results and often disappointing outcomes (2). Such drugs are available for patients with metastatic disease and its possible use as adjuvant or neoadjuvant agents Purpose: To analyze the immunohistochemical expression of the standard isoform of CD44 (CD44s) adhesion molecule in clear cell renal cell carcinoma (CCRCC) and its impact on clinical outcomes. Materials and Methods: Ninety-nine consecutive patients treated surgically for RCC between 1992 and 2009 were selected. A single pathologist reviewed all cases to effect a uniform reclassifi cation and determine the most representative tumor areas for construction of a tissue microarray. The same pathologist, who was blinded to the outcome of the cases, semi-quantitatively scored the staining intensity of CD44s in all specimens. The counting was done using the H-Score algorithm. Results: Of the 99 immunostained RCC specimens, 57(57.7%) showed low expression, and 42(42.4%) showed high expression levels of CD44s. The expression of CD44s was directly associated with tumor size (p = 0.03), clinical stage (p = 0.02) and Fuhrman grade (p = 0.02). Disease specifi c survival (DSS) rates for patients whose specimens expressed low and high levels of CD44s was 88.1% and 67.5%, respectively (p = 0.009). Progression free survival (PFS) rates in patients with low and high expression of CD44s were 78.8% and 61.7%, respectively (p = 0.05). Classical features such as the presence of metastasis and clinical stage remained isolated predictors of survival. Conclusions: Immunohistochemical expression of CD44s was associated with important clinical variables such as stage and Fuhrman grade. However, it was not an independent predictor of survival. Therefore, we believe it has a limited role as a prognostic marker in patients with CCRCC.