Background: HFS is a common toxicity of VEGF TKIs, often requiring TDRs. Correlation between HFS, in the context of TDRs, with survival outcomes has not been reported in mRCC. Methods: From a single-institutional database (2004-2013), incidence of HFS and TDRs (for any reason) in mRCC pts receiving VEGF TKIs were recorded and correlated with survival outcomes. Univariate and multivariate analyses were performed using Kaplan-Meier method and COX Proportional Hazard model. Results: Of 123 pts (median age 60 yrs, males 71%), the majority had clear cell histology (71.5%) and were in the MSKCC (71%) and Heng (55%) intermediate-risk groups. Pts received the following TKIs: sunitinib (77.2%), sorafenib (14.6%), pazopanib (7.3%), and axitinib (0.8%). HFS (G1 20.3%, G2 8.9%, G3 9.8%) occurred in 39% of pts. The most common reasons for TDRs were mucositis (38.8%), HFS (29.9%), and fatigue (17.9%). The median progression free survival (PFS) and overall survival (OS) were significantly longer in pts with HFS (Table). The median OS was improved in those who had TDRs for HFS as compared with those who had TDRs for other reasons (Table). Two multivariate analyses were conducted. The first included age, sex, HFS, TSH > 10 mIU/L while on VEGF TKI, and risk criteria. HFS remained significant for improvements in PFS and OS (PFS: HR 0.38, CI 0.19-0.76, p=0.0060; OS: HR 0.37, CI 0.15-0.83, p=0.0157). In the second multivariate analysis, development of HFS was substituted for TDRs for HFS and it was not an independent predictor of survival (PFS: HR 0.58, CI 0.25-1.23, p=0.1601; OS: HR 0.46, CI 0.16-1.14, p=0.0981). Conclusions: HFS in mRCC pts treated with VEGF TKIs predicts improved survival despite TDRs. Thus, VEGF TKI dose reductions for the management of HFS are not expected to negatively impact survival outcomes.