The effect of cigarette smoke exposure on the activity of cytosolic and microsomal epoxide hydrolase (EH) has been investigated in human lung. Patients were classified as 'recent smokers' (n = 9) or 'non-recent smokers' (n = 10) according to whether they were or were not still smoking 1 month before surgery. Cytosolic EH was measured with [³H]trans-stilbene oxide as a substrate, whereas microsomal EH was measured with [7-³H]styrene oxide as a substrate. Microsomal EH activity did not differ between recent smokers (2.51 ± 0.93 nmol min ^-1 mg^-1) and non-recent smokers (2.74 ± 1.10 nmol min ^-1 mg^-1), whereas cytosolic EH activity was significantly lower in recent smokers (6.46 ± 1.79 pmol min^-1 mg^-1) than in non-recent smokers (8.41 ± 2.09 pmol min^-1 mg^-1, P < 0.05). Cytosolic EH activity was correlated with the number of days that had passed since the cessation of smoking (r = 0.58, P < 0.05) and the effect was dose-dependent, since the enzyme activity was inversely correlated with the number of cigarettes smoked per day (r = 0.85, P < 0.01). This suggests that recent smoking exposure inhibits the activity of cytosolic EH but not microsomal EH, and that the inhibition increases with the number of cigarettes smoked per day. The contribution of cytosolic enzymes to xenobiotic metabolism may be remarkable in extrahepatic tissues. The inhibition of cytosolic EH by tobacco smoke may reduce the inactivation of carcinogenic epoxides in human lung tissues and so may increase a person's susceptibility to lung cancer.