The polymerization of methacrylic monomers present in dental composite resins never reaches completion and therefore the leakage of residual monomers into the oral cavity and into biological fluids can cause local and systemic adverse effects. This work was carried out to study the in vitro biochemical interactions of urethane dimethacrylate and 1,4-butanediol dimethacrylate monomers with HL-60 cells, a cell line assumed as an experimental model for simulating granulocyte behaviour. Our main finding was that both monomers induce cell differentiation at toxic concentrations and that cytotoxicity seems to be caused by alterations of glucose metabolism arising from mitochondrial dysfunction rather than from oxidative stress, which could not be altogether verified under our experimental conditions. Our study could be considered as a useful approach to investigate the biochemical mechanisms that contribute to the cytotoxicity of methacrylate compounds and it underlines the importance of assessing such parameters for testing biocompatibility in order to promote the development of better and safer dental materials.