Abstract: Objective: To explore the anti-hepatoma activity and related molecular mechanism of adriamycin (ADM) combined with the selective inhibitor Marinopyrrole A of myeloid cell leukemia-1 (Mcl-1). Methods: Hepatocellular carcinoma Huh7 cells and HepG2 cells were used as research objects. The inhibitory effect of ADM, Marinopyrrole A and Marinopyrrole A combined with ADM on hepatocellular carcinoma cells were detected by the methyl thiazolyl tetrazolium (MTT) assay, and the morphological changes of the cells were observed under light microscope. The apoptosis rates of cells in different treatment groups were detected by flow cytometry. The expression of multidrug resistance protein 1 (MDR1), major vault protein (MVP), Mcl-1, Cleaved poly ADP ribose polymerase (Cleaved-PARP)/PARP, Bcl-2, Bax and other drug resistance and apoptosis-related proteins was detected by western blotting. Results: The half inhibitory concentrations (IC50) of ADM on HepG2 and Huh7 cells were (3.557 ±0.640) μmol/L and (1.178 ±0.127) μmol/L, respectively. HepG2 cells were less sensitive to ADM than Huh7 cells (P＜0.01). The protein expression levels of MDR1, MVP and Mcl-1 in HepG2 cells were higher than those in Huh7 cells (all P＜0.01). Compared with the control group and ADM treatment group alone, Marinopyrrole A combined with ADM decreased the density and shrinkage of HepG2 cells, and significantly increased the rate of apoptosis, down-regulated the expression of MDR1, MVP, and Mcl-1 proteins, decreased the Bcl-2/Bax ratio, and increased the Cleaved-PARP/PARP ratio (all P＜0.05). Conclusion: The Mcl-1 inhibitor Marinopyrrole A can increase the sensitivity of hepatocellular carcinoma cells to ADM, which may be related to down-regulating the expression of drug resistance-related proteins MDR1, MVP and anti-apoptotic protein Mcl-1.