The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p less than 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p less than 0.02). In the under 40 yr group. AP clearance was higher in smokers than nonsmokers (p less than 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme-inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p less than 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug-metabolizing enzymes) but also on the effects of environmental factors, such as smoking.