Dihalomethanes are metabolized by two major pathways: an oxidative, cytochrome P-450-mediated pathway that has been previously thought to yield only CO, and a glutathione (GSH)-dependent one that yields CO 2. Both give 2 mol of halide ion. We studied the kinetic properties of the two pathways in vivo by exposing male rats to various inhaled concentrations of CH 2Cl 2, CH 2F 2, CH 2FCl, CH 2BrCl, and CH 2Br 2 and determining end-exposure carboxyhemoglobin (HbCO) and plasma bromide (where appropriate). Closed atmosphere gas uptake studies were employed for CH 2F 2, CH 2FCl, CH 2Cl 2, and CH 2BrCl metabolism. A physiologically based kinetic model was used to determine kinetic constants based on gas uptake or plasma bromide data and these constants were used to predict HbCO concentrations. Oxidation was high affinity, low capacity. The maximum metabolic rates for this pathway with CH 2Br 2, CH 2BrCl, and CH 2Cl 2 were, respectively, 72, 54, and 47 μmol metabolized/kg/hr. CH 2FCl did not undergo significant oxidative metabolism and appears more like CH 3Cl than a dihalomethane in its metabolic reactivity. The GSH pathway was low affinity, but high capacity and could be described as a single first-order process at all accessible exposure concentrations. The rate constant for this first-order GSH-dependent pathway was related as CH 2BrCl > CH 2Cl 2 ⋍ CH 2FCl > CH 2Br 2 > CH 2F 2. Presumably bromide is a preferred leaving group but steric hindrance in the initial reaction with GSH is important with CH 2Br 2. We also studied the effects of pyrazole (which inhibits microsomal oxidation) and 2,3-epoxypropanol (which depletes GSH) on dihalomethane metabolism. Pyrazole abolished CO production from CH 2Br 2, CH 2BrCl, and CH 2Cl 2. GSH depletion did not change the yield of halide ion from the high-affinity pathway; it did increase the steady-state HbCO concentrations with CH 2Cl 2 and CH 2ClBr, but not with CH 2Br 2. The putative formyl chloride (FC) intermediate from CH 2Cl 2 or CH 2BrCl appears to have a longer life than the formyl bromide from CH 2Br 2 and a significant portion of the FC (⋍20–30%) may react with other cellular nucleophiles instead of spontaneously decomposing to CO. This portion of the oxidative pathway probably yields CO 2.