NNK (4-(methylnitrosamino)―1-(3-pyridyl)-1-butanone) is a major form of nitrosamine abundant in cigarette smoke and is a powerful carcinogen. Mercury is a major component of the amalgam that is widely used as dental filling material. Concurrent exposure to these two agents may result in their interaction and alter their carcinogenic potential. The present study used an immortalized human epithelial cell system that allows continuous exposure to potential carcinogens, in an attempt to elaborate the carcinogenic potential of mercury and NNK in humans. Cytotoxicity of mercury chloride and NNK was measured by an MTT assay. Parameters of neoplastic cellular transformation such as cell saturation density, soft-agar colony formation, and cell aggregation were analyzed to examine the carcinogenic potential of mercury chloride and NNK. The study showed that exposure to mercury chloride with NNK resulted in increased soft agar colony formation and cell aggregation. ROS generation by mercury chloride was further enhanced by treatment with NNK. The apoptosis that was observed following mercury chloride exposure was further increased upon co-treatment with NNK. The interaction between these two agents was also observed in cytokine mRNA induction. In the present study, mercury alone did not seem to pose a significant threat as a carcinogen, but it may have potential to enhance the carcinogenic potential of a known carcinogen from cigarette smoke. The present study provides valuable data regarding the evaluation of potential carcinogenic risk of mercury chloride and NNK on concurrent exposure.