Cooking food at high temperatures produces genotoxic chemicals and there is concern about their impact on human health. DNA damage caused by individual chemicals has been investigated but few studies have examined the consequences of exposure to mixtures as found in food. The current study examined the mutagenic response to binary mixtures of benzo[a]pyrene (BaP) with glycidamide (GA), BaP with acrylamide (AC), or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with GA at human-relevant concentrations (sub-nM). The metabolically competent human MCL-5 cells were exposed to these chemicals individually or in mixtures and mutagenicity was assessed at the thymidine kinase (TK) locus. Mixture exposures gave dose-responses that differed from those for the individual chemicals; for the BaP-containing mixtures, an increased mutation frequency (MF) at low concentration combinations that were not mutagenic individually, and decreased MF at higher concentration combinations, compared to the calculated predicted additive MF of the individual chemicals. In contrast, the mixture of PhIP with GA did not increase MF above background levels. These data suggest BaP is driving the mutation response and that metabolic activation plays a role; in mixtures with BaP the increased/decreased MF above/below the expected additive MF the order is PhIP > AC > GA. The increase in MF at some low concentration combinations that include BaP is interesting and supports our previous work showing a similar response for BaP with PhIP, confirming this response is not limited to the BaP/PhIP combination. Moreover, the lack of a mutation response for PhIP with GA relative to the response of the individual chemicals at equivalent doses is interesting and may represent a potential avenue for reducing the risk of exposure to environmental carcinogens; specifically, removal of BaP from the mixture may reduce the mutation effect, although in the context of food this would be significantly challenging.