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%). Here, TFE3 is linked to renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.