Background: Three large randomized placebo controlled trials (RCTs) (ASSURE, S-TARC, PROTECT) with adjuvant VEGF-TKIs in high risk RCCs have provided variable results for improving disease free survival (DFS) with concerns for increased toxicity. We performed a meta-analysis of these trial results to asses a risk-benefit for adjuvant post-op treatments in high risk RCC patients by assessing reported disease free survival (DFS) and toxicity endpoints. Methods: A generic variance weighted random effects model was used to derive estimates for DFS and common side effects in the three trials. A separate analysis was performed for Sunitinib alone because of its FDA approval. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I²test. I²> 75% was consistent with a high degree of heterogeneity. Results: The three RCTs involved 4096 patients. Adjuvant therapy with TKIs yielded no significant improvement in DFS or OS as compared to placebo (DFS HR = 0.92, 95% CI 0.82-1.04 and OS HR = 1.00, 95% CI 0.86-1.17). Separate analysis of DFS in sunitinib vs placebo did not show any benefit (2 studies, N = 1909; HR = 0.90, 95% CI 0.67-1.19). Use of TKIs was associated with significantly increased risk of drug toxicity. Increased risk of grade 3 or 4 adverse events (RR = 2.73, 95% CI 2.51-2.97), diarrhea (RR = 14.57, 95% CI 7.93-26.79), fatigue (RR = 3.63, 95% CI 2.13-6.18), hypertension (RR = 3.95, 95% CI 3.18-4.91) and palmar/plantar dysesthesia (RR = 21.4, 95% CI 12.91-35.47) was observed. Conclusions: No OS or DFS benefit for VEGF TKIs including for Sunitinib was observed in this meta-analysis, while there was a significantly increased risk of toxicity in greater than half of the patient population. Subgroup analyses based on age, sex, pharamacokinetics, pharmacogenomics may help to identify potential candidates. Analysis from ongoing adjuvant TKI trial results (SORCE,ATLAS,2810) and immunotherapy (IMMotion,Keynote-564,checkmate 914) are awaited and may provide more refinement in selecting high risk RCC candidates with favorable benefit-risk ratios for post op drug therapies.