There is a strong association between depression and smoking. Because monoamine oxidase (MAO) inhibition leads to antidepressant effect and in vitro studies have shown that cigarette smoke inhibits MAO activity, it is conceivable that smoking may have an antidepressant effect, if smokers have reduced MAO activity. Therefore, we assessed platelet MAO-B activity and plasma concentration of catecholamine metabolites reflecting MAO-A activity in heavy dependent smokers and nonsmokers matched for sociodemographic characteristics. Platelet MAO-B activity, plasma 3,4-dihydroxyphenylglycol, plasma 3,4-dihydroxyphenylacetic acid, and plasma 3,4-dihydroxyphenylalanine concentrations were significantly lower in smokers than in nonsmokers, whereas plasma norepinephrine did not differ. Significantly more smokers reported previous history of depression, manic episode, panic attack, agoraphobia, and simple phobia. Smokers had higher scores (p < 0.001) on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Scales. It is concluded that the activities of both forms of the MAO are reduced in heavy dependent smokers.