Background: Circulating tumor DNA (ctDNA) profiling is a non-invasive method to genomically assess solid tumors. Key benchmarks are required to assess applications in RCC management. To evaluate this tool broadly, we performed a large cohort analysis using a comparative approach to correlate clinical characteristics and matched oncogenomics of primary tumor and ctDNA. Methods: Pts with prior NGS sequenced mutational profiles from tumor (nephrectomy or metastatic tissues) underwent a single-time point plasma collection for ctDNA extraction. ctDNA targeted NGS sequencing was performed using MSK-IMPACT, with bi-directional cross genotype comparison using Waltz 2.0. Liberal (1-2 reads) and stringent (≥3 reads) filters were applied, with a cut-off of <30% allele frequency to remove germline alterations. Relevant clinical parameters were analyzed for correlation with ctDNA alteration frequency and load. Results: 110 metastatic clear-cell RCC pts, of whom available IMDC-risk was favorable (25%), intermediate (45%), or poor (4%) were included. 96% of pts had a nephrectomy prior to ctDNA collection, and most were heavily pre-treated (mean: 3 therapies, R: 0-8). The median time from diagnosis to ctDNA collection was 22.1 months (R: 2.3-215), and the median time from site specific tissue sequencing was 23.8 months (R: 1-177). 587 alterations were identified across the entire cohort in primary tissues, and 65% of pts had ≥1 alteration in ctDNA by liberal criteria. Detection rates for VHL and PBRM1 alterations were different in primary tissue and ctDNA (both liberal and stringent) with VHL altered in 92%, 43% and 50%, respectively; and PBRM1 altered in 50%, 25%, 21%, respectively. Conclusions: This large cohort analysis shows comparable mutational profiles of RCC-specific alterations in primary tissue and ctDNA, and highlights challenges of liquid biopsy approaches in RCC. Future efforts to correlate clinical outcomes with algorithm-based metrics will enhance the utility of this tool.