Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy. Display omitted •Sarcomatoid differentiation of RCC is associated with distinct epigenomic programs•FOSL1 is associated with clinical outcomes of immunotherapy in RCC•FOSL1 induces sRCC gene expression changes in epithelioid ccRCC•Epigenomic liquid biopsy detects signatures of sarcomatoid differentiation from blood El Zarif et al. present a comprehensive epigenomic characterization of sarcomatoid renal cell carcinoma (sRCC). They establish associations between FOSL1 gene expression and clinical outcomes to immunotherapy in RCC. In a proof of concept, they developed an epigenomic liquid biopsy technique that enables the detection of sRCC in blood.