Dopamine and norepinephrine are key regulators of cognitive and affective processes. The enzyme catechol-O-methyltransferase (COMT) catabolizes catecholamines and the COMT Val158Met polymorphism has been linked to several neuropsychiatric variables. Additionally, stressful life events (SLEs) contribute substantially to affective processes. We used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the effects of COMT and SLEs on the cortisol response in 119 healthy children (8-12 yr). Saliva cortisol was measured during and after the Trier Social Stress Test for Children. SLEs were assessed with a standardized interview with one of the children's parents. Linear regression analysis revealed a significant effect for COMT, with Met allele carriers showing a higher cortisol response (β=0.300, p=0.001). In turn, more SLEs lead to a less pronounced cortisol increase (β=-0.192, p=0.029) probably indicating increased resilience. Our results further underscore the essential and differential role of genetic variation and environmental factors on stress responsivity.