Comorbidity is common among patients with major depression, but in most instances it may be of little relevance. Nonetheless, it is a complex issue because of its relation to treatment response, and few studies have attempted to address this. Most have examined comorbidity after the fact in secondary analyses. In this article, I focus on whether comorbidity influences depression treatment response among patients who are primarily diagnosed as suffering from major depression. At least three comorbidities are believed to influence treatment response: medical, anxiety, and personality disorders. Whether studies find that these factors predict worse outcomes in patients with major depression appears to depend on the nature and severity of the medical illness, the study setting, and the study design. The best designed studies reported the least effects of these factors on treatment outcome. Clinically, this suggests that these factors should not be seen as impediments to treatment.