Highlights 1. Circulating exosomal RNA sequencing identified novel potential biomarkers of clear cell renal cell carcinoma (ccRCC). 2. The early diagnostic signature comprising KMT2D and PREX2 showed high accuracy in distinguishing ccRCCs from healthy individuals. 3. The differential diagnostic signature comprising CUL9, KMT2D, and PREX2 showed great performance in distinguishing ccRCCs from benign renal masses. 4. These signatures could be promising and noninvasive biomarkers for ccRCC detection.