Background: There are no available data on the usefulness of targeted therapy (TT) as the first-line treatment for patients with RCC recurrence after AS. We aim to explore the outcomes of systemic therapy with recurrent RCC after AS including re-exposure to sunitinib. Methods: A multi-institutional retrospective study was conducted on RCC patients who relapsed after AS. The primary end point was progression-free survival (PFS). Secondary end points were overall response rate (ORR) and overall survival (OS). Results: 34 relapses were recorded, 25 patients (73,5%) were male. 25 patients were treated with systemic therapy at first-line after relapse: 65% of patients received Vascular Endothelial Growth Factor (VEGF)-TT (including 7 patients retreated with sunitinib), 21,7% mTOR inhibitors and 13% immunotherapy. The median time to relapse was 20,3 months (IQR 5,2-20,4) from diagnosis, and 7,5 months (IQR 1,0-8,5) months from AS ending. At a median time of follow-up of 23,5 months, 24/25 patients had progressed on first-line systemic therapy. The median PFS was 12,0 months (IC95% 6,6-17,8 months). There was no statistical difference in PFS among the different treatments or the re-exposed to sunitinib. PFS was not statistically different between those relapsing on or after AS ( < 6 or > 6 months after AS). ORR was 20,3%. Median OS was 28,7 months (IC95% 24,4-33,0). Conclusions: This study suggests that TT may still improve PFS and OS in RCC patients who relapsed after AS.