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Background: Antisocial behaviour has been associated with polymorphic variants in candidate genes and recently also gene-environmental interaction models have been presented. It has been suggested that antisocial behaviour, associated with alcohol consumption in males, is related to a variation in the monoamine oxidase A gene (MAO-A) promoter. Furthermore, platelet MAO-B activity has in several studies been reported to be low in male alcoholics, while this has not been the case with regard to female alcoholics. Aims of the present study were to: (1) investigate possible interactions between the MAO-A polymorphism, family relations and maltreatment/sexual abuse on adolescent alcohol-related problem behaviour among female adolescents; (2) to investigate if platelet MAO-B enzyme activity interacted with environment to predict female alcohol-related problems. Methods: A random sample of 114 female individuals from a total population of 16- and 19-year adolescents from a Swedish county, who volunteered to participate in the study, were interviewed, filled in a questionnaire and a blood sample was drawn. Results: In contrast to what has been reported in males, presence of the long (4-repeat) variant of the MAO-A gene in females interacted significantly with an unfavourable environment (poor family relations or maltreatment/abuse/sexual abuse) to increase the risk for high scores of alcohol-related problems. Furthermore, females with low platelet MAO-B activity showed an increased risk of alcohol-related problem behaviour in an unfavourable environment. Conclusions: Poor psychosocial environment interacts with the high activity MAO-A genotype and low platelet MAO-B enzyme activity to increase vulnerability for female adolescent alcohol-related problem behaviour.