Platelet monoamine oxidase (MAO) activity is a marker of personality and psychiatric vulnerability, but the direct inhibitory action of tobacco constituents on the enzyme distorts the association. In the present investigation, data from a prospective longitudinal study of smoking behaviour and platelet MAO activity in adolescents at ages 15 and 18 years were sequentially analysed using a second-order multiple logistic regression analysis. The odds of regular smoking at 18 years increased significantly with increasing absolute deviation of platelet MAO activity at 15 years from the mean. That is, both low and high platelet MAO activity at 15 years predicted a higher probability of becoming a smoker. These data suggest that smoking is associated with low platelet MAO activity not only because of the direct inhibitory effect of tobacco constituents on the enzyme, but also because subjects with low platelet MAO activity are more likely to become smokers. Furthermore, the possible association between above-average platelet MAO activity and behavioural phenotypes should be reexamined.