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Summary Background An unmet medical need exists for patients with metastatic renal cell carcinoma (RCC) who have progressed on a vascular endothelial growth factor (VEGF)–targeted therapy plus a mammalian target of rapamycin (mTOR) inhibitor. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine kinase inhibitor that inhibits VEGF and FGF receptors. This open-label, multicenter phase 3 study compared dovitinib with sorafenib as a third-line targeted therapy in metastatic RCC. Methods Patients (N = 570) with clear cell metastatic RCC who received one prior VEGF-targeted therapy and one prior mTOR inhibitor were randomized 1:1 to receive dovitinib (500 mg orally on a 5-days-on/2-days-off schedule) or sorafenib (400 mg orally twice daily). Randomization was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) by central review. Secondary endpoints included overall survival (OS) and safety. Biomarker studies were an exploratory endpoint. Findings The median PFS was 3·7 months for dovitinib (n = 284) and 3·6 months for sorafenib (n = 286) (hazard ratio [HR], 0·86; 95% CI, 0·72-1·04; one-sided P = 0·063). Median OS was 11·1 months for dovitinib and 11·0 months for sorafenib (HR, 0·96; 95% CI, 0·75-1·22). Diarrhea, nausea, and vomiting were more common with dovitinib, whereas palmar-plantar erythrodysesthesia, hypertension, and alopecia were more common with sorafenib. In both arms, prolonged OS was observed in patients with low baseline plasma levels of FGF2, hepatocyte growth factor, and VEGFA. Interpretation Dovitinib demonstrated activity but not superior efficacy compared with sorafenib in patients who progressed on prior VEGF-targeted therapies and mTOR inhibitors. This trial provides landmark outcome data for future studies in this third-line setting. Funding Novartis Pharmaceuticals Corporation