OBJECTIVES: To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres-sed patients with and without comorbid medical illness. SETTING: Multicenter. DESIGN: Randomized, double-blind, placebo-controlled study. PARTICIPANTS: A total of 752 patients aged 60 and older with diagnosis of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis. MEASUREMENTS: Outcome measures included the 17-item Hamilton Depression Scale (HAMD); the Clinical Global Depression-Severity/Improvement (CGI-S/CGI-I); efficacy and safety/adverse event assessments; Quality of Life, Enjoyment, and Satisfaction Questionnaire; and the Medical Outcomes Study 36-Item Short-Form Health Status Survey. RESULTS: In the overall sample, sertraline was superior to placebo on all three primary outcome measures, HAMD, and overall clinical severity and change (CGI-S/CGI-I). Furthermore, therapeutic response to sertraline was comparable in those with or without medical comorbidity, and there were no treatment-by-comorbidity group interactions. Sertraline was also associated with a faster time to response than placebo in the comorbid group (P<.006). Sertraline-treated patients in the comorbid group had similar adverse events and discontinuations when compared to those in the noncomorbid group. CONCLUSION: Sertraline was efficacious in reducing depressive symptomatology, regardless of the presence of comorbid medical illness. Sertraline was safe and well tolerated by patients with or without medical illness.