Background: Previous studies have suggested a link between plasma cytokines and mRCC outcomes with systemic therapy. In a prospective study, we assessed whether plasma cytokines could separately predict outcome with immunotherapy or targeted therapy. Methods: Eligible patients (pts) had histologically proven mRCC with intent to receive a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or an immune checkpoint inhibitor (ICI). Immunologic profiles were evaluated at several time points using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit (CB) was defined as complete response, partial response, or stable disease ≥ 6 months. Results: A total of 56 pts (40:16 M:F) were enrolled; 23 pts and 33 pts received VEGF-TKI and ICI, respectively. The most common VEGF-TKI was cabozantinib; the most common ICI was nivolumab. CB was similar between VEGF-TKI and ICI arms (65% vs 54%). Pts with CB from VEGF-TKIs had lower pretreatment levels of IL-6 (p = 0.02), IL-1RA (p = 0.03), and G-CSF (p = 0.02). Major shifts in plasma cytokines were seen as early as one month; these data will be presented. Conclusions: Distinct plasma cytokines predict benefit with VEGF-TKIs and ICIs. Ongoing work will incorporate analysis of pts receiving VEGF-TKI and ICI combination therapy.