To explore the extent to which treatment of depression affects survival, we evaluated the association between use of antidepressant medications and death rates among the residents of a large residential-care facility for the elderly using a retrospective record-review study (N = 624). One year survival, among those taking antidepressants (10.9%), was 11.8% compared to 11.1% among the remainder of the population. A second study followed a group of 32 patients in the same institution who had participated in a therapeutic trial of nortriptyline treatment for major depression. Patients who experienced adverse medical events during treatment exhibited significantly increased mortality; among treatment completers, there was no significant relationship between mortality and therapeutic response. These findings suggest that the inability to tolerate treatment with an antidepressant can be considered a manifestation of physiologic frailty and increased vulnerability to mortality from disease. The previously reported decrease in survival among residential-care patients with major depression is not paralleled by a similar effect in those taking antidepressants. This may reflect selection factors with respect to the ability to tolerate antidepressants, rather an effect of treatment.