Volatile halogenated aliphatic compounds are among those chemicals that can cause oxidative stress in vitro and in vivo. Relationships can be identified between the potential of these chemicals to elicit certain biological responses and their specific chemical descriptors, such as molecular orbital energies (LUMO) or partition coefficients (logP). A quantitative structure-activity relationship (QSAR) model has not been reported previously for the potential of a series of brominated and chlorinated methanes to induce oxidative stress in primary rat hepatocytes. By utilizing a novel in vitro methodology to expose cultures of rat primary hepatocytes to volatile chemicals, biological responses were assessed from exposures of hepatocytes to individual halogenated methanes. Indicators of lipid peroxidation, reactive oxygen species and cytotoxicity were measured. For the 10 brominated and chlorinated methanes tested, semi-empirical molecular orbital methods were used to calculate the physical/chemical descriptors used in the QSAR models. These models were used to explain the relative potential for a given halogenated methane to induce markers of oxidative stress or related damage in vitro. The results showed that certain descriptors, such as the molecular orbital energies, bond lengths, and lipophilicity are quantitatively correlated with induction of indicators for oxidative stress and cytotoxicity by halogenated methanes in primary rat hepatocytes.