Parathion and chlorpyrifos are phosphorothionate insecticides, but parathion is substantially more toxic than chlorpyrifos to rats, and both are more toxic to females than to males. A kinetic analysis of cytochrome P-450 mediated desulfuration (activation) and dearylation (detoxication) of the two insecticides indicated that rat hepatic microsomes have a higher capacity to activate and a lower capacity to detoxify parathion than chlorpyrifos; these capacities correspond to their acute toxicity levels. Greater capabilities of both activation and detoxication were found in males than in females for both insecticides, which is especially apparent by comparing the clearance terms (Vmax/Km). Since dearylation clearances, but not desulfuration clearances, correspond with the sex differences in toxicity levels of the two compounds, dearylation may be the more important factor in determining the acute toxicity level. An extrapolation of lethal dose levels of the two insecticides to concentrations that could be encountered in a severe intoxication indicated that activation of both insecticides could readily occur; however, the dearylation of chlorpyrifos, but not of parathion, would occur readily. This difference in the likelihood of dearylation could be an important contributor to the lower acute toxicity levels of chlorpyrifos.