Objectives. Methacrylate monomers have been identified in aqueous extracts of freshly cured compomers. Both cells in the pulpal cavity and various cells of the oral mucosa can potentially be exposed to these leachables. Short-term exposure to dental monomers at relatively high concentrations induces adverse biological effects in vitro. The mechanisms involved have not been fully elucidated although involvement of various signaling pathways including ROS formation, activation of MAP-kinases and caspases has been suggested. The aim of this study was to investigate potential cellular responses following long-term exposure to relatively low and potentially more clinical relevant HEMA concentrations. Methods. A submandibular gland cell line was exposed to HEMA (20-600 mu M) for up to 72 h. The impact on cell proliferation, apoptosis, and possible underlying mechanisms was assessed by flow cytometry, microscopy and western blotting. Results. Exposure to HEMA (600 mu M) resulted in reduced cell proliferation after 24 h and increased apoptosis after 60 h. Further, we observed ATM dependent phosphorylation of p53, advocating an initial DNA damage in the HEMA exposed cells. Significance. In conclusion, we show that exposure to relatively low concentration of HEMA for a prolonged time result in cell death, possibly as a consequence of DNA damage. (c) 2007 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.