The amygdala plays a central role in various aspects of affect processing and mood regulation by its rich anatomical connections to other limbic and cortical regions. It is plausible that depressive disorders, and response to antidepressant drugs, may reflect changes in the physiological coupling between the amygdala and other components of affect-related large-scale brain systems. We explored this hypothesis by mapping the functional coupling of right and left amygdalae in functional magnetic resonance imaging data acquired from 19 patients with major depressive disorder and 19 healthy volunteers, each scanned twice (at baseline and 8 weeks later) during performance of an implicit facial affect processing task. Between scanning sessions, the patients received treatment with an antidepressant drug, fluoxetine 20 mg/day. We found that the amygdala was positively coupled bilaterally with medial temporal and ventral occipital regions, and negatively coupled with the anterior cingulate cortex. Antidepressant treatment was associated with significantly increased coupling between the amygdala and right frontal and cingulate cortex, striatum, and thalamus. Treatment-related increases in functional coupling to frontal and other regions were greater for the left amygdala than for the right amygdala. These results indicate that antidepressant drug effects can be measured in terms of altered coupling between components of cortico-limbic systems and that these effects were most clearly demonstrated by enhanced functional coupling of the left amygdala.