Background: ICIs have improved survival in mRCC patients (pts), yet response rates (RR) to these treatments are variable. Biomarkers predictive of response to ICIs may improve outcomes for mccRCC pts. Genes that promote tumor-specific iron accumulation such as hepcidin (HAMP) or transferrin (TF) are significantly correlated with decreased overall survival in clear cell RCC (TCGA-KIRC). Iron deficiency in cancer patients is positively correlated with tumor stage and inversely proportional to treatment response (PMID: 23567147). Here, we investigate whether serum iron profile may be associated with response to ICIs in mccRCC pts. Methods: Clinical data was obtained from an mRCC registry at the Huntsman Cancer Institute, University of Utah. Analyses were limited to mccRCC pts who had serum iron studies within 6 months before initiating an ICI and had been assessed for RR. ICIs included nivolumab + ipilimumab, atezolizumab, or nivolumab alone. Responses were defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) by RECIST criteria. Clinical benefit (CB) was defined as CR + PR + SD. Descriptive statistics were used to assess associations between iron stores and response to ICIs and IMDC criteria. Results: 36 pts met all aforementioned eligibility criteria (29 were of IMDC intermediate risk, 7 were of IMDC poor risk). 5 pts received a first-line ICI, and the remaining 31 pts received ICIs as salvage therapy. Pts with CB had a significantly higher median serum iron level compared to those with no CB (59 vs 38.5 ug/dL; p=0.024). Furthermore, pts with normal transferrin saturation (TSAT %) were more likely to derive CB from ICIs (p=0.048). No association was found between serum ferritin (a marker of inflammation and tissue iron) and response to ICIs. Conclusions: In this hypothesis-generating study, increased serum iron, and TSAT levels within the normal range are associated with an increased likelihood of response to ICIs in pts with mccRCC. Once validated, these results may establish serum iron profile as a predictive marker of response to ICIs, in addition to providing the rationale for ruling out iron deficiency before starting ICIs.