OBJECTIVES: To estimate direct costs associated to grades 3-4 adverse events (AEs) management treatment of metastatic renal cell carcinoma (mRCC) with targeted therapies (sorafenib, sunitinib, pazopanib, bevacizumab, everolimus and temsirolimus) and to perform a comparative analysis from public and private healthcare perspectives, in Brazil. METHODS: A systematic literature review was conducted to identify grades 3-4 AEs related to targeted therapies. To obtain direct costs related to AEs management, procedures were created from national guidelines and expert validation. Total cost for each drug was calculated, considering a six-month time horizon. Only direct medical costs were considered, expressed in 2011 Brazilian reals (BRL). Unit costs were obtained from Brazilian official lists. As no head-to-head trials were found, indirect comparison in second-line targeted therapy was performed according to NCCN guideline for everolimus (grade 1 recommendation) versus sorafenib and sunitinib (grade 2A) and temsirolimus (grade 2B). Bevacizumab (grade 2B) was excluded as data was available only for the association with IFN. In the base case, grades 3-4 incidence rates were obtained from phase III clinical trials and varied in sensitivity analysis based on results obtained in meta-analyses or observational studies. RESULTS: When compared to NCCN 2A recommendation grade for second-line targeted therapy, everolimus is cost-saving in base case and sensitivity analysis: versus sorafenib, there are savings ranging from 5BRL to 717BRL and from 96BRL to 5841BRL in public and private perspectives, respectively; versus sunitinib, savings vary from 153BRL to 681BRL and from 1778BRL to 5136BRL in public and private perspectives, respectively. Everolimus was cost-saving due to easily manageable AEs and their frequencies. CONCLUSIONS: Considering grades 1 and 2 NCCN recommendation for mRCC second-line targeted therapies, everolimus represents the highest quality of evidence and is also considered the lowest cost option for the management of associated AEs from public and private healthcare perspectives, in Brazil.