This study used a case-control design to address differences in psychosocial, physical and clinical profiles between subjects who presented with a chronic index episode of major depression and those who presented with a non-chronic index episode. Subjects were adult patients participating in the Duke University Mental Health Clinical Research Center (MHCRC) for the Study of Depression in Later Life. Cases (N = 88) who reported duration of depressive symptoms lasting > or = 24 months at enrollment were compared to controls (N = 354) who reported symptoms lasting 1-12 months. The groups were compared with respect to selected demographic and clinical variables, physical function deficits, medical comorbidity, social support constructs and number of recent stressful life events. Social support and physical health were more relevant to chronicity of major depressive illness than were severity of illness or family history. Older age (> 60 years) intensified the deleterious effect of recent negative life events and reduced the deleterious effect of functional impairment on chronic major depression. These findings require special emphasis where treatment for chronic major depression is divorced from considerations of the social environment and functional capacity.