In renal cell carcinoma (RCC), single members of the Wnt/beta-catenin signaling cascade were recently identified to contribute to cancer progression. However, the role of Wnt1, one of the key ligands in beta-catenin regulation, is currently unknown in RCC. Therefore, alterations of the Wnt1/beta-catenin axis in clear cell RCC (ccRCC) were examined with regard to clinicopathology, overall survival (OS) and cancer specific survival (CSS). Corresponding ccRCCs and benign renal tissue were analyzed in 278 patients for Wnt1 and beta-catenin expression by immunohistochemistry in tissue microarrays. Expression scores, including intensity and percentage of stained cells, were compared between normal kidney and ccRCCs. Data was categorized according to mean expression scores and correlated to tumor and patients' characteristics. Survival was analyzed according to the Kaplan-Meier and log-rank test. Univariable and multivariable Cox proportional hazard regression models were used to explore the independent prognostic value of Wnt1 and beta-catenin. In ccRCCs, high Wnt1 was associated with increased tumor diameter, stage and vascular invasion (p <= 0.02). High membranous beta-catenin was associated with advanced stage, vascular invasion and tumor necrosis (p <= 0.01). Higher diameter, stage, node involvement, grade, vascular invasion and sarcomatoid differentiation (p <= 0.01) were found in patients with high cytoplasmic beta-catenin. Patients with a high cytoplasmic beta-catenin had a significantly reduced OS (hazard ratio (HR) 1.75) and CSS (HR 2.26), which was not independently associated with OS and CSS after adjustment in the multivariable model. Increased ccRCC aggressiveness was reflected by an altered Wnt1/beta-catenin signaling. Cytoplasmic beta-catenin was identified as the most promising candidate associated with unfavorable clinicopathology and impaired survival. Nevertheless, the shift of membranous beta-catenin to the cytoplasm with a subsequently increased nuclear expression, as shown for other malignancies, could not be demonstrated to be present in ccRCC.