Widespread application of silica nanoparticles (nSiO) and ubiquitous metalloid arsenic (As) may increase their chances of co-exposure to human beings in daily life. Nonetheless, studies on combined effects of nSiO and As in human cells are lacking. We investigated the co-exposure effects of nSiO and As in human liver (HepG2) and human fibroblast (HT1080) cells. Results showed that nSiO did not cause cytotoxicity. However, exposure of As caused oxidative stress and apoptosis in both types of cells. Interesting results were that co-exposure of a non-cytotoxic concentration of nSiO significantly augmented the As induced toxicity in both cells. Intracellular level of As was higher in the co-exposure group (nSiO + As) than the As group alone, suggesting that nSiO facilitates the cellular uptake of As. Co-exposure of nSiO and As potentiated oxidative stress indicated by pro-oxidants generation (reactive oxygen species, hydrogen peroxide and lipid peroxidation) and antioxidants depletion (glutathione level, and glutathione reductase, superoxide dismutase and catalase activities). In addition, co-exposure of nSiO and As also potentiated mitochondria-mediated apoptosis suggested by increased expression of , , and genes (pro-apoptotic) and decreased expression of gene (anti-apoptotic) along with depleted mitochondrial membrane potential. To the best of our knowledge, this is the first study showing that co-exposure of nSiO and As induced augmentation of oxidative stress and mitochondria-mediated apoptosis in HepG2 and HT1080 cells. Hence, careful attention is required for human health assessment following combined exposure to nSiO and As.