Background: Everolimus is currently the only approved second-line therapy in VEGF-TKI (sunitinib or sorafenib) refractory mRCC patients following recent findings from the RECORD-1 clinical trial in which everolimus was compared with best supportive care. There is, however, a lack of data comparing everolimus to other second line therapies in this setting. This study aims to compare sorafenib and everolimus for second-line treatment of sunitinib-refractory mRCC patients. Methods: An indirect comparison was employed by examining everolimus patients who had failed prior sunitinib treatment from the RECORD-1 trial and sorafenib patients from the recently published phase II study of sunitinib-refractory mRCC patients in Italy (Di Lorenzo, 2008). While most baseline characteristics were similar in the two study populations, there was a significant difference in baseline MSKCC score (77% vs. 28% low risk for sorafenib and everolimus patients, respectively). A ranuni function in SAS was used to match the two populations on risk score distributions. OS and PFS estimates were compared between treatment arms and the instantaneous hazard rates for each treatment arm were calculated and defined as the rate per patient per day. A 6-year Markov cohort simulation model was also used to estimate the difference in total life-years (LY) for patients treated with everolimus vs sorafenib for potential use in cost-effectiveness (CE) analysis. Results: The final study population consisted of 46 everolimus patients and 52 sorafenib patients with equivalent distributions of MSKCC score. The estimated incremental LY gained for failed sunitinib patients treated with everolimus versus with sorafenib was 1.135 years. Conclusions: In sunitinib-refractory mRCC patients there may be a PFS and OS benefit with the use of everolimus compared to sorafenib. It would be valuable to examine the necessary cost to achieve the additional LY gained through CE analysis.