Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene-involved in monoaminergic neurotransmission-as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD. © 2012 Macmillan Publishers Limited All rights reserved.