Toxicological interaction represents a challenge to toxicology, particularly for novel contaminants. There are no data whether silver nanoparticles (AgNPs), present in a wide variety of products, can interact and modulate the toxicity of ubiquitous contaminants, such as nonessential metals. In the current study, we investigated the toxicological interactions of AgNP (size=1-2nm; zeta potential=-23mV), cadmium and mercury in human hepatoma HepG2 cells. The results indicated that the co-exposures led to toxicological interactions, with AgNP+Cd being more toxic than AgNP+Hg. Early (2-4h) increases of ROS (DCF assay) and mitochondrial O2(-) levels (Mitosox® assay) were observed in the cells co-exposed to AgNP+Cd/Hg, in comparison to control and individual contaminants, but the effect was partially reverted in AgNP+Hg at the end of 24h-exposure. In addition, decreases of mitochondrial metabolism (MTT), cell viability (neutral red uptake assay), cell proliferation (crystal violet assay) and ABC-transporters activity (rhodamine accumulation assay) were also more pronounced in the co-exposure groups. Foremost, co-exposure to AgNP and metals potentiated cell death (mainly by necrosis) and Hg(2+) (but not Cd(2+)) intracellular levels (ICP-MS). Therefore, toxicological interactions seem to increase the toxicity of AgNP, cadmium and mercury.