OBJECTIVES: Metastatic renal cell carcinoma (mRCC) is highly resistant to chemotherapeutics, rendering limited anti-tumor effect. New treatments such as Sunitinib, Sorafenib, Bevacizumab/Interferon-alpha (INF-alpha), and Temsirolimus have been recently licensed for first-line treatment of patients with mRCC. We assessed the cost-effectiveness of these therapies from the perspective of the Israeli healthcare payer. METHODS: We used a Markov model with a 10-year time horizon to simulate disease progression, survival, and cost outcomes for a hypothetical cohort of mRCC patients. Although no head-to- head trials comparing the new treatment modalities are available, most studies had compared the new therapies against INF-alpha, thus allowing an indirect comparison of clinical efficacy. Utility weights were estimated from Sunitinib clinical trials using the EQ-5D. Drug and other healthcare costs were estimated from nationally published sources, and reported in 2008 New Israeli Shekels (NIS). Treatment effectiveness was measured in QALYs gained. Costs and benefits were discounted annually at 3%. We used a series of univariate and probabilistic sensitivity analyses to test the robustness of our base-case findings. RESULTS: Sunitinib was the most effective intervention and resulted in a gain of 0.27 QALYs compared with Sorafenib and 0.08 QALYs gained compared with Bevacizumab/ INF-alpha or Temsirolimus. The total discounted drug cost for treating mRCC patients was 277,184 NIS for Sorafenib, 380,749 NIS for Temsirolimus, 343,712 NIS for Sunitinib, and 420,987 NIS for Bevacizumab/INF-alpha. Treating patients with Sunitinib resulted in an ICER of 245,869 NIS (~$60,000) per QALY gained when compared with Sorafenib, and was the dominant intervention compared to the other treatment modalities. The model results were robust to changes in a wide range of model parameters, including treatment efficacy and follow-up treatment costs. CONCLUSIONS: Our model indicates that Sunitinib is a cost-saving alternative, when compared with Bevacizumab/INF-alpha, and Temsirolimus and is within the accepted threshold for cost-effective interventions when compared with Sorafenib.