Background: The predictive role of metastatic sites in RCC pts treated with tyrosine kinase inhibitors (TKIs) is unclear. Aim of this study was to investigate whether first line SU and SO was associated to metastatic sites in terms of progression-free survival (PFS) and overall survival (OS). Methods: A retrospective cohort of consecutive metastatic RCC (mRCC) pts treated with TKIs at Istituto Nazionale Tumori of Milan was analyzed. All pts received at least one targeted therapy including: SO, SU, bevacizumab plus interferon-alfa, pazopanib or temsirolimus. The product limit method was used to estimate survival functions and Cox regression to estimate hazard ratios (HRs) and to test statistical interaction between sub-groups identified by different metastatic sites. Results: 358 mRCC pts receiving first line TKIs between January 2005 and October 2012 were evaluated. Overall 206 pts (58%) received SO while 103 pts (29%) SU. Median duration of treatment for SU and SO groups was 16 (95%CI 12.0-20.1) and 9 months (mo) respectively (95%CI 7.0-12.0). After a median follow-up of 56.1 mo (range: 1.0-93.2) median OS for SO group was 19.9 mo (95%CI 16.0-25.1) while OS for SU group was not yet defined. Noteworthy 142 pts (69%) treated with SO received SU at disease progression (PD) while 36 pts (35%) received SO at SU failure. A statistically significant interaction between first line treatment and metastatic sites was found for the liver site in terms of PFS and OS (PFS p=0.034; OS p=0.004). SU was associated with a 18% [95%CI (-37%)- 123%] higher risk of PD as compared to SO in pts with liver mets while pts without liver mets showed a 46% [95%CI (-61%)-(-24%)] decreased risk of PD as compared to SO. SU was associated with a 40% [95%CI (-32%)-187%] higher risk of death as compared to SO in pts with liver mets while pts without liver mets showed a 62% [95%CI (-76%)-(-40%)] decreased risk of death as compared to SO. The predictive role of liver mets was confirmed introducing the Motzer score (PFS p=0.084; OS p=0.009). Conclusions: mRCC pts with liver mets treated with first line SO showed a better outcome as compared to SU while pts without liver mets treated with first line SO showed a worse outcome as compared to SU.