Background: Arsenic trioxide (As2O3) is widely used for the treatment of acute promyelocytic leukemia (APL), and more recently, has also been applied to solid tumors. However, there are a fraction of patients with solid tumors, such as liver cancer, who respond to As2O3 treatment poorly. The underlying mechanisms for this remain unclear. Methods: We determined the suitable concentration of drugs by IC50. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to analyze the apoptosis. Morphological changes of the cells were observed by laser scanning confocal microscopy. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Quantitative polymerase chain reaction (qPCR) and Western blot tests were conducted to detect the mRNA and protein levels in different groups. Finally, a xenograft tumor assay and histopathological analysis were performed to evaluate the MARVELD1 function in cell proliferation and apoptosis. Results: Here, we show that MARVELD1 enhances the therapeutic effects of epirubicin, while inducing the strong resistance of liver cancer cells to As2O3 treatment. We further demonstrate that the As2O3-induced apoptosis was inhibited by MARVELD1 overexpression (24 h Vector vs. MARVELD1 =30.58% vs. 17.41%, P<0.01; 48 h Vector vs. MARVELD1 =46.50% vs. 21.02%, P<0.01), possibly through inhibiting ROS production by enhancing TRXR1 expression. In vivo, we found a significantly increased size (Vector vs. MARVELD1=203.90 +/- 21.92 vs. 675.70 +/- 37.84 mm(3), P<0.001) and weight (Vector vs. MARVELD1 =0.19 +/- 0.02 vs. 0.58 +/- 0.05 g, P<0.001) of tumors with high expression of MARVELD1 after As2O3 treatment. Consistently, a higher expression of MARVELD1 predicted a poor prognosis for liver cancer patients. Conclusions: Our data identified a unique role of MARVELD1 in As2O3-induced apoptosis and As2O3 cancer therapy resistance.