Background: A randomized phase II trial evaluating So plus IL-2 versus So alone as first-line treatment of mRCC, did not show any difference in progression-free survival (PFS) (primary endpoint) between the two groups. The final overall survival analysis is here reported. Methods: In this open-label phase II study, 128 patients with mRCC were randomized to receive either oral So 400 mg bid continuous dosing plus IL-2 4.5 MIU subcutaneously administered 5 times weekly for 6 weeks every 8 weeks (Arm A), or So alone (Arm B). At relapse, most patients of the two arms underwent treatment with other targeted therapies (TTs) including sunitinib, everolimus, and axitinib. Overall survival was estimated by Kaplan-Meier method and compared by two-sided log-rank test. Results: According to Motzer criteria 55 % of the patients were low risk in both arms, and 41% and 39% were intermediate risk in Arm A and B respectively. After a median follow-up time of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in Arm A and B, respectively (p = 0.667). Five-year OS was 26.3% (95% CI: 15.9-43.5) for the combination arm and 23.1% (95% CI: 13.2-40.5) for single agent arm. The overall number of death was 85, 42 of whom in the So monotherapy group. Median PFS survival was 7.3 and 6.9 months for Arm A and B, respectively (p = 0.109). Overall, 49 (77%) and 48 (75%) patients in Arm A and B, respectively, received at least one subsequent targeted therapy (TTs). The most common adverse events (AEs) in both arms were asthenia, hand-foot syndrome, hypertension and diarrhoea. Grade 3-4 AEs were documented in 38% of patients treated with the combination regimen and in 25% of those undergoing single agent treatment. Conclusions: The OS results suggest an improved outcome in patients with mRCC treated with TTs which appears independent of the treatment initially administered. This prospective study, regarding use of sorafenib in first line of treatment, was associated with a surprising median OS. Clinical trial information: NCT00609401.