Abstract Background Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor ( BDNF ) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction. Methods A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method. Results The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression ( P  = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events ( P  = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity ( P  = 0.051). Conclusions The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.