The authors examined the impact of comorbid medical illness on the rate of relapse of major depressive disorder during continuation therapy. Subjects (N = 128) with major depressive disorder (according to DSM-III-R criteria) achieved clinical remission (a 17-item Hamilton Depression Rating Scale score < or = 7) after 8 weeks of treatment with fluoxetine and entered the continuation phase of antidepressant treatment. They used the Cumulative Illness Rating Scale to measure the severity of comorbid medical illness. Eight patients (6.3%) relapsed during the 28-week continuation phase. With logistic regression, the total burden and the severity of comorbid medical illness significantly predicted the relapse of major depressive disorder during continuation therapy with fluoxetine. Greater medical comorbidity was also associated with higher increases in self-reported symptoms of depression, anxiety, and anger during the follow-up.