Since multiple front-line immune checkpoint inhibitor-based (ICI-based) combinations are approved for metastatic renal cell carcinoma, biomarkers predicting for ICI responses are needed past clinical prognostication scores and transcriptome gene expression profiling. Circulating markers represent opportunities to assess baseline and dynamic changes in immune cell frequency and cytokine levels while on treatment. We conducted an exploratory prospective correlative study of 33 patients with metastatic clear cell renal cell carcinoma undergoing treatment with ICIs and correlated changes in circulating immune cell subsets and cytokines with clinical responses to treatment. Cell frequencies and cytokine levels were compared between responders and nonresponders using unpaired parametric t tests, using prespecified alpha level of significance of 0.05. Classical monocyte subsets (CD14+CD16-), as well as 7 cytokines (IL-12/23 p40, macrophage inflammatory protein-1a, macrophage inflammatory protein-1b, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, IL-8, and TNF-α) were higher at baseline for responding versus nonresponding patients. Dynamic changes in thymus- and activation-regulated chemokine (TARC), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) also correlated with patients with ICI response. In summary, macrophage-activating agents were observed to be important in ICI response and may highlight the importance of the innate immune response in ICI responses.