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TFE3 translocation renal cell carcinoma (tRCC), an aggressive kidney cancer driven by TFE3 gene fusions, is frequently misdiagnosed owing to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays that detect tumor DNA via somatic mutations or copy number alterations are unsuitable for tRCC since it often lacks recurrent genetic alterations and because fusion breakpoints are highly variable between patients. We reasoned that epigenomic profiling could more effectively detect tRCC because the driver fusion constitutes an oncogenic transcription factor that alters gene regulation. By defining a TFE3-driven epigenomic signature in tRCC cell lines and detecting it in patient plasma using ChIP-seq, we distinguished tRCC from clear-cell RCC (AUC = 0.86) and samples of individuals without evidence of cancer (AUC = 0.92) at low tumor fractions (<1%). This work establishes a framework for noninvasive epigenomic detection, diagnosis, and monitoring of tRCC, with implications for other mutationally quiet, fusion-driven cancers.