OBJECTIVES: To assess the cost-effectiveness of first line metastatic renal cell cancer (mRCC) drugs from the perspective of two different economic and clinical settings, the Netherlands (NL) and Serbia (SRB). METHODS: The research included all first line mRCC therapeutics recommended by the European and American guidelines: sunitinib, pazopanib, bevacizumab and temsirolimus. Clinical efficacy data were extracted from published pivotal and head-to-head studies. Costs were described with regards to the treatment protocols of NL and SRB. A Markov model was designed to incorporate efficacy and costs data per each therapeutic alternative. An annual discount rate of 1.5% for health and 4% for costs was applied and a healthcare perspective was taken. Probabilistic sensitivity analysis (PSA) was performed to test the uncertainty around the base-case estimate. RESULTS: With the incremental cost-effectiveness ratio (ICER) of €44,512 and €39,625/QALY in NL and SRB respectively, sunitinib was the most cost-effective therapeutic alternative, followed by pazopanib, temsirolimus and bevacizumab. Incremental costs were comparable in SRB and NL and mainly controlled by the drugs’ price. All estimated ICERs appeared lower within Serbian economic surrounding. PSA revealed a wide confidence interval around the base-case ICERs highly dependent on potential gain in overall survival (OS). CONCLUSIONS: The base-case ICERs calculated for NL were below the commonly accepted threshold recommended by WHO (three times national GDP per capita for QALY or €95,700/QALY in NL), indicating the relative cost-effectiveness of examined mRCC drugs. However, none of these pharmaceuticals could be regarded as cost-effective under the same criterion in SRB (threshold of €14,400/QALY). Although between-the-setting variation resulted in lower ICERs in SRB, this could not compensate for the sevenfold difference in countries’ incomes. Finally, two main parameters that might increase cost-effectiveness of mRCC drugs in mid-income countries seem to be the drug prices and their potential benefit in OS.