Cadmium (Cd), a common and widespread toxic heavy metal, and mycotoxins such as deoxynivalenol (DON) are frequent contaminants of the food supply. Most of the data on their toxicity concern their effects when present alone. However, consumers can be exposed to a cocktail of DON and Cd. To improve the understanding of their combined toxicity, the effects of DON and Cd alone or in combination were investigated in different human cell lines from the kidney (HEK-293), intestine (Caco-2), blood (HL-60) and liver (HepG2). Cytotoxicity was assessed through ATP measurement and types of interactions determined by the Isobologram-Combination index method. HEK-293 cells were exposed to increasing doses of DON, Cd and their combination at different ratios (DON/Cd of 2/1; 1/1; 1/2 and 1/8). Regardless of the ratio, the type of interaction observed in HEK-293 cells ranged from moderate antagonism to nearly additive with increasing cytotoxicity. In Caco-2 cells, the interactions ranged from nearly additive to antagonism whatever the ratio. At ratio 1/1, in HL-60 and HepG2 cells, interactions ranged from synergy to antagonism depending on the cytotoxicity level. Using human cells lines, this study indicates that the consequences of combined exposure to environmental and food contaminants are specific to the target organ. Further studies are needed to confirm these data in vivo.