Affective facial processing is an important component of interpersonal relationships, which is altered in patients with major depression. The study was designed to examine differences in functional brain activity between patients with major depression and healthy controls using functional magnetic resonance imaging (fMRI). Twelve patients with major depression and 12 age-, gender- and handedness-matched healthy controls were studied using fMRI. Subjects had to match facial emotional expressions in explicit trials, and gender of the presented faces in implicit trials. Patients showed higher blood oxygen level-dependent (BOLD) responses to implicit emotional stimuli than healthy controls in the left dorsolateral prefrontal cortex and the left precentral gyrus. Patients show a failure of deactivation in ACC, right dorsolateral prefrontal cortex (DLPFC) and right superior frontal cortex. Moreover, they exhibited smaller differences in BOLD responses in the left superior temporal lobe for the implicit contrasted to the explicit task, and in the cerebellum for the explicit contrasted to the implicit task compared to those of controls. Altered activation of the prefrontal cortex and anterior cingulum during emotion processing is a key feature of major depression.