Illness course separates patients with atypical depression into tricyclic responders and nonresponders as does perceptual asymmetry. The authors therefore investigated whether the course-of-illness parameters would define groups within atypical depression differing in brain laterality. Patients with atypical depression were assessed for illness course and brain laterality. Two patient groups were defined, 1 with onset prior to age 20 plus a very chronic course, and a 2nd group having later onset or less chronic illness. Patients reporting early onset of very chronic dysphoria showed significantly less right-ear (left-hemisphere) accuracy and also differed in characteristic perceptual asymmetry when compared to patients with later onset or less chronicity. Course of illness may usefully define more homogeneous depressive subgroups within atypical depression.