This study examined whether stroke lesions involving left hemisphere prefrontal or basal ganglia structures are associated with poststroke depression. A consecutive series of first-ever stroke patients with single small lesions on CT scan were examined for the presence and severity of poststroke depressive disorder. Lesions involving left prefrontal or basal ganglia structures were compared with other left hemisphere lesions and all right hemisphere lesions. Forty-one patients were examined. Patients with lesions involving left hemisphere prefrontal or basal ganglia structures had a higher frequency of depressive disorder (9/12; 75%) than other left hemisphere lesions (1/12; 8%) or those with right hemisphere lesions (5/17; 29%), P = 0.002. These findings suggest that damage to neural pathways within left hemisphere prefrontal or basal ganglia structures is associated with depressed mood following stroke.