Background: Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction. Methods: Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed. Results: We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT(p = 0.019): MAOA (p = 0.044) and COMT(p = 0.026), and MAOAxCOMT (p Conclusion: We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the G x E concept for depression, but they underline the complexity of this concept as the cumulating effects of these polymorphic genes (i.e. MAOA + COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods. (C)2009 Elsevier Inc. All rights reserved.