Background: Approximately 20-30% of patients (pts) with renal cell carcinoma (RCC) develop recurrence after treatment of localized disease. Of these pts, the great majority recur within the first few years following surgery. Rarely, late recurrences are seen after 5 years of disease free survival. The outcome of metastatic RCC has improved markedly with targeted therapies (TT). Little data are available about outcomes of pts with metastatic RCC from late recurrences who are treated with TT. Methods: We retrospectively reviewed records of consecutive pts with metastatic RCC who had late recurrence >5 years and were treated with TT between 11/1/2006 and 11/1/2013. All the pts had prior nephrectomies. Outcomes were tabulated using basic statistical techniques. Adverse events (AEs) were graded using CTCAE v4.0. Results: 24 pts (100% clear-cell, median age 69 years, 83% males, all with prior nephrectomies) met inclusion criteria with late recurrence >5 years. 79% had favorable risk and 21% intermediate risk by MSKCC criteria. 11 pts died. Estimated median overall survival time for all pts was 50.2 months (95% CI: 23.93–NR) .The 3-year overall survival rate was 71.78% (95% CI: 47.98-84.77). The median number of sequential TT received was 2 (range 1-4). Median time on first line TT was 20.7 months. 45% of pts received pazopanib in the frontline setting, 29% received sunitnib, and 25% received sorafenib. 68% received TT in the second-line and subsequent settings. Common adverse events of TT included fatigue (52%), diarrhea (36%), hypertension (36%), anorexia (28%), hair and skin changes (24%), increased liver function tests (20%), nausea/vomiting (16%), and 95% of adverse events were grade 1/2. Conclusions: In this retrospective study, pts diagnosed with metastatic RCC after disease free interval >5 years have prolonged survival when treated with TT. Overall survival and 3-year survival rates were better than historical controls. Adverse events were mild/moderate and manageable.