This study assessed the effect of general medical comorbidity on response to next-step antidepressant treatments among subjects with major depressive disorder whose depression failed to respond to an 8-week open trial of 20 mg/day of fluoxetine. Of the 386 outpatients in the open trial, 101 who remained depressed were randomly assigned to double-blind treatment with either an increased dose of fluoxetine or lithium or desipramine augmentation for 4 weeks. The Cumulative Illness Rating Scale (CIRS) was used to assess baseline general medical comorbidity, and the Hamilton Depression Rating Scale was used to assess depressive symptoms. Logistic regression analysis showed that CIRS score was not associated with likelihood of remission or premature study discontinuation. Medical comorbidity thus does not appear to be associated with significantly poorer outcome among patients whose major depressive disorder failed initially to respond to an initial trial of 20 mg/day of fluoxetine.