The functional Val158Met polymorphism in the gene coding for the catechol-O-methyltransferase (COMT), the major enzyme degrading the catecholaminergic neurotransmitters dopamine, norepinephrine, and epinephrine, has been associated with differential reactivity in limbic and prefrontal brain areas in response to aversive stimuli. However, studies on COMT-genotype effects on activity of the amygdala, a brain region centrally involved in affective processing, have yielded inconsistent results. Here we investigated the impact of the COMT Val158Met polymorphism on amygdala activity and connectivity during processing of emotional and neutral pictures using functional magnetic resonance imaging (fMRI) in 56 healthy participants. Homozygosity for the low-activity Met allele was positively correlated with increased activation in the right amygdala in response to unpleasant, but not pleasant pictures. In addition, the Met allele exerted an additive effect on the positive connectivity between the right amygdala and orbitofrontal regions. Our results support previous reports of a COMT-genotype-dependent difference in amygdala responsivity as well as connectivity, and highlight the importance of naturally occurring genetic variations in the catecholaminergic system for neural activity underlying affective processing.