Background: VEGFR TKIs are important therapeutic agents in RCC, but their adjuvant use remains limited. Investigating the effects of these medications on circulating angiogenic factors and cytokines in the adjuvant setting can elucidate whether changes in cytokine levels result from drug-host or drug-tumor interactions, and may reveal biomarkers to guide patient selection for adjuvant treatment. Methods: In the ECOG-ACRIN 2805 (ASSURE) trial, patients with resected RCC were randomized to sunitinib, sorafenib, or placebo. Plasma was collected at start of treatment and 4 or 6 weeks after treatment initiation. All paired samples available by July 2010 were analyzed, corresponding to 413 patients. We analyzed VEGF, PlGF, sFlt1, KDR/sVEGFR-2, Ang2, bFGF, HGF, IFNg, IL8, CXCL9, CXCL10, and CXCL11. Mixed effects models were used to test for changes from baseline. Cox models were used to assess associations between disease-free survival (DFS) and angiogenic factor and cytokine levels. Results: VEGF and PlGF increased after 4 weeks on either treatment (p < 0.0001 for both), and at 6 weeks VEGF and PIGF levels returned to baseline for patients on sunitinib (corresponding to the 2 week break in the sunitinib schedule) but not sorafenib. Levels of sFLT-1 decreased after 4 weeks on suntinib and after 6 weeks on sorafenib (p < 0.0001). sVEGFR2 decreased after both 4 and 6 weeks of treatment on both sunitinib and sorafenib (p < 0.0001). Patients on placebo had no significant changes in circulating angiogenic factor or cytokine levels. CXCL-10 levels increased after 4 weeks on both sunitinib and sorafenib but not on placebo, and remained elevated at 6 weeks on sunitinib. Higher baseline CXCL-10 was associated with worse DFS (HR 1.41 per log increase in CXCL-10, Holm adjusted p-value 0.003, 95% CI 1.18-1.70). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG PS. Conclusions: Among patients treated with VEGFR TKIs in the adjuvant setting for RCC, drug-host interactions mediate changes in cytokines and angiogenic factors. Elevated CXCL-10 prior to treatment was associated with higher recurrence risk. Studies to understand the functional consequences of these changes are underway.