OBJECTIVES: Bevacizumab (BEV) + Interferon-alpha-2a (IFN-α) and sunitinib (SUN) have shown significant increase in progression free survival (PFS) compared to IFN-α in first-line metastatic renal cell carcinoma (mRCC) therapy. There is no head-to-head evidence available comparing both regimens, however there is an increasing need to assess and compare the relative efficacy and effectiveness of both therapy approaches. METHODS: We applied the widely accepted indirect comparison method (Bucher et al. J Clin Epidemiol 1997) to PFS data of the pivotal phase III trials, that is, the unadjusted investigator-assessed PFS hazard ratios (HR) for BEV+IFN-α vs. IFN-α (0.63) and for SUN vs IFN-α (0.52). To enable valid indirect comparison, the IFN-α control arms of both trials have been standardised by recalculating the indirect HR and transferring them into direct HR estimates using the cross-trial proportions. In addition, we adjusted for effects of down-dosing and patient compliance based on published evidence. Sensitivity analyses on adjustment components have been performed. RESULTS: The unadjusted indirect efficacy comparison resulted in a statistically non-significant PFS difference of SUN vs BEV+IFN-α (HR: 0.82; 95% CI: 0.64-1.06; p=0.13). Standardising the IFN arms and simulating realistic scenarios for SUN down-dosing and patient compliance results in similar PFS HRs for BEV+IFN-α (HR: 0.63) and Sunitinib (HR: 0.64) as compared to IFN alone. The adjusted indirect PFS HR of SUN vs BEV + IFN-α was 1.025 (95% CI: 0.81-1.30; p=0.83). Results were mostly influenced by IFN-α control arm adjustment, followed by patient compliance and down-dosing. CONCLUSIONS: Based on our comparative effectiveness evaluation in first-line mRCC therapy, there is no statistically significant evidence for a difference in efficacy and effectiveness regarding PFS between BEV+IFN-α and SUN. These findings imply that additional treatment decision criteria such as tolerability need to be considered to guide treatment decisions.