The interaction between anxiety disorder and major depressive disorder in patients with cerebrovascular lesions was examined in a controlled, 2 x 2 study design. A consecutive series of 24 patients who met criteria for major depression only were compared with 6 patients who met criteria for both major depression and generalized anxiety disorder, and 45 patients who did not meet criteria for either major depression of generalized anxiety. Among patients with positive computed tomographic scans, the anxious-depressed group (n = 19) showed a significantly higher frequency of cortical lesions, while patients with major depression only (n = 15) had a significantly higher frequency of subcortical (basal ganglia) strokes. No significant between-group differences were found in other variables, such as demographic variables, familial and personal history of psychiatric disorders, and neurologic deficits. These findings suggest that, in this mostly black, low-socioeconomic-status population, cortical vs subcortical lesion location may play an important role in determining whether severe anxiety occurs in patients with post-stroke major depression.