The present study investigates the influence of long-term ethanol (ETOH) treatment of rats [10% (v/v) for 4, 12, and 36 weeks] on the metabolism of DCM after its oral and inhalative uptake to CO. Biotransformation of DCM to CO as measured by carboxyhemoglobin (COHb) formation was stimulated after long-term ETOH treatment in rats. A single oral dose of DCM (6.2 mmol/kg body mass) caused a significant increase of COHb, the maximum of about 9% occurring approximately 6 hr after DCM administration. In comparison to this control, in the blood of rats pretreated with ETOH (10% v/v) for 4, 12, and 36 weeks COHb values of 18, 17, and 13%, respectively, were measured. Long-term ETOH treatment followed by inhalation of 100, 500, and 2500 ppm DCM for 4 hr stimulated the formation of COHb, compared to controls. The elevation of COHb level was accompanied by decreased concentrations of DCM in the blood. The reason for the elevated biotransformation of DCM was ascertained by means of the determination of p-nitrophenol and aniline hydroxylation in liver microsomes of rats after long-term ETOH treatment to be an increase in cytochrome P450-dependent enzyme activities.