We have recently found that millimolar concentrations of sodium fluoride (NaF) induced apoptotic cell death, characterized by caspase activation and DNA fragmentation, in tumor cell lines. This finding paved the way to investigating the interaction between NaF and the oral environment. As an initial step, we investigated redox compounds, metals and saliva, which may modify the cytotoxic activity of NaF against a human oral squamous cell carcinoma cell line (HSC-2). The minimum exposure time to NaF required for cytotoxicity induction was 8 hours. Noncytotoxic concentrations of antioxidants (sodium ascorbate, gallic acid, epigallocatechin gallate, chlorogenic acid, curcumin, superoxide dismutase, catalase), oxidants (hydrogen peroxide, sodium hypochlorite), metals (CuCl, CuCl2, FeCl2, FeCl3, CoCl2) or saliva neither protected against, nor enhanced the cytotoxic activity of NaF. Cytotoxic concentrations of these compounds produced somewhat additive, but not synergistic, effects on the cytotoxicity of NaF. ESR analysis demonstrated that NaF did not apparently change the radical intensity of sodium ascorbate and gallic acid, measured under alkaline conditions. During the cell death induction in human promyelocytic leukemia HL-60 cells by NaF, the consumption of glucose rapidly declined, followed by a decline in the consumption of major amino acids. The present study suggests that the cytotoxic activity of NaF is not regulated by the redox mechanism, but rather linked to the rapid decline in glucose consumption at early stage.