Background: Hispanic patients with renal cell carcinoma (RCC) have worse clinical outcomes than non-Hispanic White (NHW) patients. It is unclear if this disparity is related to biological differences or social determinants of health (SDOH). There is limited knowledge about potential genetic variations in RCC between these ethnic populations. Methods: Patients with metastatic ccRCC evaluated at UCSD were retrospectively identified from chart review or a single institutional database. Patients with genomic sequencing on tissue samples from primary kidney and/or metastatic sites were included for analysis. Patients were categorized as non-Black Hispanic or NHW based on self-identification. Logistic regression was applied for the presence of divergent frequencies of somatic mutations. Cox regression models evaluated the effect of additional factors on overall mortality, with correction for multiple tests using Benjamini-Hochberg method. Results: The analysis included 103 patients with metastatic ccRCC, of whom 46% were Hispanic. We did not observe statistically significant differences in median age at diagnosis (61 vs 62 years), BMI (28 in both), proportion of males (74% vs 73%), never smokers (47% vs 56%), sarcomatoid component (24% vs 17%), receipt of systemic therapy (92% vs 96%) or treatment initiated after 2017 (57% vs 56%) between Hispanic and NHWs. There were also no differences in the number or locations of metastases between ethnic groups. Hispanics were more likely to have public health insurance (34% vs 9%, p<0.01) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) intermediate/poor risk disease (81% vs 55%, p<0.01). Hispanics had a higher frequency of BAP1 mutations (28% vs 7%, p=0.01) compared to NHWs, whereas NHWs had more frequent TP53 (24% vs 4%, p=0.01) and SETD2 alterations (29% vs 4%, p<0.01). VHL (80% vs 74%, p=0.51) and PBRM1 (26% vs 36%, p=0.34) mutations were comparable between Hispanic and NHWs. First-line treatment regimens were similar between the two groups: tyrosine kinase inhibitor (TKI) monotherapy (45% vs 42%), immunotherapy (IO/IO) doublet (23% vs 27%) and combined IO/TKI (15% vs 11%). On multivariable analysis, there was a significant difference in OS between Hispanic and NHWs (HR 3.60, 95%CI 1.49-8.67, adjusted p= 0.04) after correcting for age, sex, smoking, insurance, IMDC risk group, number of metastatic sites, sarcomatoid feature, therapy regimen and VHL, PBRM1, SETD2, TP53 and BAP1 mutations. Conclusions: We demonstrated a marked association in survival outcomes and differences in the mutational landscape of ccRCC between Hispanic and NHW patients. These findings underscore the interplay between genetic variations and social determinants, especially given the observed insurance disparities. Our study emphasizes the need for further research in ccRCC across diverse ethnicities.