In this study, we showed that SOX8 might play an important role in regulating drug resistance in GTN cells, as knockdown of SOX8 could attenuate drug resistance through reducing cell viability, impairing soft agar clonogenesis, and inducing apoptosis following drug treatment in JEG3 chemoresistant sublines. The gene discussed is SOX8; the disease is gestational trophoblastic neoplasm.