We used functional magnetic resonance imaging (fMRI) to determine whether depressed (vs non-depressed) adults showed differences in cortical activation in response to stimuli representing personal goals. Drawing upon regulatory focus theory as well as previous research, we predicted that depressed patients would manifest attenuated left orbitofrontal cortex (OFC) activation in response to their own promotion goals as well as exaggerated right OFC activation in response to their own prevention goals. Unmedicated adults with major depression (n = 22) and adults with no history of affective disorder (n = 14) completed questionnaires and a personal goal interview. Several weeks later, they were scanned during a judgment task which (unknown to them) included stimuli representing their promotion and prevention goals. Both groups showed similar patterns of task-related activation. Consistent with predictions, patients showed significantly decreased left OFC and increased right OFC activation compared to controls on trials in which they were exposed incidentally to their promotion and prevention goals, respectively. The results suggest that depression involves dysfunction in processing two important types of personal goals. The findings extend models of the etiology of depression to incorporate cognitive and motivational processes underlying higher order goal representation and ultimately may provide an empirical basis for treatment matching.