OBJECTIVES: To assess the cost-effectiveness of axitinib compared to sorafenib from the perspective of a US third-party payer for second-line treatment of patients with advanced RCC who failed cytokines. METHODS: Phase III AXIS trial reported that axitinib increased median progression free survival (PFS) compared to sorafenib (12.0 vs. 6.6 months, p<0.0001), while overall survival (OS) showed no difference (29.4 vs. 27.8 months, p=0.144) in patients failing treatment with cytokines. A cohort partition model was constructed to estimate direct medical costs and health outcomes, discounted at 3.0% per annum. Patients were apportioned into 3 health states (progression-free, progressed and dead) based on OS and PFS Kaplan-Meier curves from the AXIS trial.  Active treatment was applied until progression, followed by best supportive care (BSC) thereafter. The wholesale acquisition costs and adverse event (AE) costs were obtained from published sources. AE rates and utility values were informed by the AXIS trial. US administrative claims data (MarketScan®) was analyzed to estimate routine care costs. Probabilistic sensitivity analysis (PSA) was conducted. RESULTS: The total per-patient lifetime costs were estimated to be $242,750 for axitinib and $168,880 for sorafenib and 84% of the cost difference was due to the higher total medication cost of axitinib. The quality-adjusted life-years (QALY) gained on axitinib vs. sorafenib was 1.3 vs. 1.2 and the incremental cost-effectiveness ratio (ICER) was $683,209/QALY. 100% of the PSA iterations showed that axitinib was more expensive than sorafenib and the QALY difference between axitinib and sorafenib was no greater than 0.7. CONCLUSIONS:  For post-cytokine subgroup, axitinib resulted in an ICER > $650,000/QALY versus sorafenib due to high drug costs and lack of OS benefit, indicating that axitinib may not present good value for money as 2nd line treatment of advanced RCC when compared to sorafenib in the US.