SummaryIn contrast to the study of clinical heterogeneity in patients with functional (i.e., no known neuropathology) mood disorder, the study of clinical heterogeneity of mood disorder in patients with stroke has the advantage of providing another variable (i.e., lesion size or location) which can be correlated with clinical presentation. We have demonstrated the utility of this kind of correlation by presenting several studies in which heterogeneity in clinical presentation was found to correlate with site of lesion. Patients with major depression and prominent anxiety were significantly more likely to have left cortical lesions than patients with major depression without anxiety symptoms, who were more likely to have left subcortical (basal ganglia) lesions. Similarly, patients whose depression spontaneously remitted within six months had a significantly higher frequency of subcortical or brainstem lesions, compared to those without early remission, who had cortical lesions. Finally, patients with bipolar disorders were significantly more likely to have right subcortical (basal ganglia or thalamic) lesions than patients with mania only, who were more likely to have right orbitofrontal or basotemporal lesions. These findings suggest that there may be an underlying neuroanatomical and/or neurophysiological explanation for these differences in clinical presentation.