Environmental electrophiles readily interact with reactive sulfur species (RSS), resulting in decline of cellular RSS levels accompanied by formation of their sulfur adducts. In the present study, we examined the effects of combined environmental electrophiles on consumption of persulfide and on cytotoxicity in HepG2 cells. A convenient assay with SSP4, a fluorometric probe for detection of per/polysulfides, indicated that each environmental electrophile caused compound-dependent consumption of persulfide. Consumption of persulfide by combined exposure to methylmercury (MeHg) and cadmium (Cd) was greater than that of the single exposure. Consistent with this finding, combined exposure to environmental electrophiles (MeHg, Cd, and 1,4-naphthoquinone) exacerbated concentration-dependent cellular toxicity in HepG2 cells compare to single exposure to each compound. As humans are exposed to environmental electrophiles daily, more attention should be paid to the study of combined exposure to environmental electrophiles, which can modulate cellular levels of RSS and disrupt redox homeostasis.