All the methylation markers, including the two panels, showed a very high positive predictive value, ranging from 96.6% to 100%, which suggested that SHOX2, RASSF1A, SEPTIN9, and HOXA9 promoter methylation detection in pleural effusion could be effective complementary tools for cytology in the differential diagnosis of MPE. Here, HOXA9 is linked to Pleural effusion.