Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR) recommended for patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor (VEGF) receptor-tyrosine kinase inhibitor therapy. Efficacy of everolimus in patients who progressed on anti-VEGF monoclonal antibody bevacizumab is unknown. We did a multicenter prospective trial of everolimus in patients with mRCC whose disease had progressed on bevacizumab ± interferon alpha (IFN). Patients with clear-cell mRCC which had progressed on bevacizumab ± IFN received everolimus 10 mg once daily. The primary end point was the proportion of patients remaining progression-free for 56 days, and a two-stage Simon design was used, with 80% power and an alpha risk of 5%. This study is registered with ClinicalTrials.gov, number NCT02056587. From December 2011 to October 2013, a total of 37 patients (28 M, 9 F) were enrolled. Median age was 60.5 years (range 41-66), 1% had Eastern Cooperative Oncology Group Performance Status (ECOG PS) >2, and Memorial Sloan-Kettering Cancer Center (MSKCC) favorable/intermediate risk was 38/62%. Five (14%) patients had a confirmed partial response and 26 (70%) patients had a stable disease. Median progression-free survival was 11.5 months (95% CI, 8.8-14.2). Median overall survival was not reached. No grade 3 or 4 treatment-related toxicities were observed. The most common grade 2 adverse events were fatigue (19%) and pneumonitis (8%). Everolimus demonstrated a favorable toxicity profile and promising anti-tumor activity as a second-line therapy in metastatic renal cell carcinoma (RCC) patients previously treated with bevacizumab ± IFN.