Serum EV-SF3B4 showed better performance in diagnosing early HCC (CH/LC vs. mUICC I; AUC, 0.910 and 0.940 for cohort 3 and external cohort, respectively) than AFP (AUC, 0.635 and 0.785 for cohort 3 and external cohort, respectively). This evidence concerns the gene AFP and cyclic hematopoiesis.