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Background: In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma., Methods: In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT00920816., Findings: Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months [95% CI 7·2-12·1] vs 6·5 months [4·7-8·3], respectively; stratified hazard ratio 0·77, 95% CI 0·56-1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 [50%] of 189 patients vs 38 [40%] of 96 patients), hypertension (92 [49%] vs 28 [29%]), weight decrease (69 [37%] vs 23 [24%]), decreased appetite (54 [29%] vs 18 [19%]), dysphonia (44 [23%] vs ten [10%]), hypothyroidism (39 [21%] vs seven [7%]), and upper abdominal pain (31 [16%] vs six [6%]); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 [39%] of 96 patients vs 50 [26%] of 189), rash (19 [20%] vs 18 [10%]), alopecia (18 [19%] vs eight [4%]), and erythema (18 [19%] vs five [3%]). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 [14%] of 189 patients), diarrhoea (17 [9%]), asthenia (16 [8%]), weight decrease (16 [8%]), and PPE (14 [7%]); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 [16%] of 96 patients), diarrhoea (five [5%]), and asthenia (five [5%]). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib., Interpretation: Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile., Funding: Pfizer Inc., (Copyright © 2013 Elsevier Ltd. All rights reserved.)