Background: A small body of research suggests that gene–environment interactions play an important role in the development of bipolar disorder. The aim of the present study is to contribute to this work by exploring the relationship between stressful life events and the catechol-O-methyl-transferase (COMT) Val158Met polymorphism in bipolar disorder. Methods: Four hundred eighty-two bipolar cases and 205 psychiatrically healthy controls completed the List of Threatening Experiences Questionnaire. Bipolar cases reported the events experienced 6 months before their worst depressive and manic episodes; controls reported those events experienced 6 months prior to their interview. The genotypic information for the COMT Val158Met variant (rs4680) was extracted from GWAS analysis of the sample. Results: The impact of stressful life events was moderated by the COMT genotype for the worst depressive episode using a Val dominant model (adjusted risk difference = 0.09, 95% confidence intervals = 0.003–0.18, P =.04). For the worst manic episodes no significant interactions between COMT and stressful life events were detected. Conclusions: This is the first study to explore the relationship between stressful life events and the COMT Val158Met polymorphism focusing solely on bipolar disorder. The results of this study highlight the importance of the interplay between genetic and environmental factors for bipolar depression.