Background: Kidney cancer is diagnosed in approximately 270,000 people each year worldwide, and results in 120,000 deaths, with RCC as the most common form. Up to 30% of patients treated by nephrectomy for localized disease will relapse. 5-year survival rates for TNM stage II, III and IV are 65-80%, 40-60% and 0-20%, respectively. RCC is a high VEGF- and PDGF-expressing tumor. Axitinib, an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is approved for the treatment of advanced RCC after failure of one prior systemic therapy. Preclinical data indicate higher potency and selectivity against the VEGFR family for axitinib compared to some other antiangiogenic agents. This phase 3 study tests the hypothesis that prevention of micro-metastases and tumor growth by anti-VEGF treatment with axitinib can prolong disease free interval after nephrectomy for patients with high risk of recurrent RCC. Methods: 692 patients, ECOG PS 0-1, with histologically confirmed preponderant clear cell RCC; treatment naïve and no residual or metastatic disease after nephrectomy will be randomized 1:1 to axitinib or placebo, 5mg PO BID for up to 3 years in a global, randomized, double blind placebo controlled trial. Patient will be stratified according their country and their stage of disease (any Fuhrman grade allowed): 1) pT2, pN0 or pNx, M0; 2) pT3, pN0 or pNx, M0; 3) pT4, pN0 or pNx, M0; or 4) any pT, pN1, M0; and ECOG PS 0-1. Primary objective is disease free survival as assessed by independent review committee. Key secondary objectives are overall survival as well as safety and tolerability of treatment. Efficacy analysis will be performed on the intention-to-treat population. This is a global, multi-center study with sites in Asia, US and Europe. As of January 2014, 167 subjects have been randomized and last patient enrollment is expected at the end of 2014. Clinical trial information: NCT01599754.