Dihalomethanes are metabolized to carbon monoxide (CO) both in vivo and in vitro. The reaction is catalyzed by the hepatic microsomal cytochrome P-450 dependent mixed function oxidase system. Reaction mechanism studies suggest an initial oxygen insertion reaction followed by rearrangement to a formyl halide intermediate, which in turn decomposes to yield CO. In vitro studies show that [14C]dichloromethane becomes covalently bound to both microsomal protein and lipid. The similar characteristics of metabolism to CO and covalent suggest that a common intermediate, perhaps the formyl halide, may be involved. Dihalomethanes are also metabolized for formaldehyde, formic acid, and inorganic halide. A glutathione transferase located in hepatic cytosol fractions appears to be involved. Reaction mechanism studies suggest that a S-hydroxymethyl glutathione intermediate may yield formaldehyde or be diverted via formaldehyde dehydrogenase/S-formyl glutathione hydrolase to yield formic acid. Haloforms are also metabolized to carbon monoxide both in vivo and in vitro by a hepatic microsomal cytochrome P-450 dependent mixed function oxidase system. In vitro, this reaction is markedly stimulated by sulfhydryl compounds. Reaction mechanism studies suggest an initial oxygen insertion reaction followed by rearrangement to a dihalocarbonyl intermediate, which in turn reacts with sulfhydryl reagents to yield a thiol-S-formyl halide. Subsequent attack by other sulfhydryl compounds would result in the formation of CO and a disulfide.