Background: Targeted Therapies (TTs) have definitely improved survival in patients with mRCC. However the optimal therapeutic strategy is not shared. This study was performed to assess the overall survival (OS) in a consecutive series of mRCC patients receiving TTs. Methods: Characteristics and outcomes of 336 patients affected by mRCC receiving TTs were collected from the database of Istituto Nazionale Tumori of Milan. The main characteristics of patients were: ECOG PS 0/1/2 186 (55%)/131 (39%)/19 (6 %); clear-cell histology 291 (87%); previous nephrectomy 293 (87%). According to Motzer criteria 32% of patients showed low risk, 48% intermediate risk and 20% poor. Overall, 167 (50%) patients received one TTs, while 116 (34%), 42 (13%) and 11 (3.3%) received 2, 3 and 4 TTs, respectively. 245 (73%) patients received sorafenib (So), 212 (63%) sunitinib (Su), 33 (10%) a bevacizumab regimen and 73 (22%) other TTs, including everolimus, temsirolimus and axitinib. The Kaplan Meier curves were used to describe the survival.The uni- and multi-variate analyses for OS were carried out by means of Cox proportional hazard regression analysis. Results: Ata median follow-up of 43 months, 199 patients (57 %) had died. The median OS was 24 months (95%CI: 20.0-27.0) and the 5-year OS was 24.6 % (95 %CI: 18.7-30.8). In univariate analyses, there were no significant differences in the hazard ratios (HR) for So followed by Su compared to Su followed by So (HR_{SU-SO / SO-SU} = 1.16; 95%CI: 0.57-2.33) or compared with other therapies (HR_{Other sequential th. / SO-SU} = 1.21; 95%CI: 0.78-1.88; p=0.674).In the multivariate analysis, in terms of OS any statistical difference was reported as regards the sequence used (Su/So vs So/Su; p>0.05) or bevacizumab regimen as compared to Su and/or So used sequentially (p>0.05). In the uni and multivariate analysis ECOG PS, nephrectomy, Fuhrman grade and number of sites of disease are independent predictive factors of outcome (p< 0.01). Conclusions: These data suggest that TTs improve OS in mRCC without any statistical difference when using different sequences of TTs. No cross-resistance between several sequences of TTs was documented.