Background: There is conflicting evidence about comorbid personality pathology in depression treatments. Aims: To test the effects of antidepressant drugs and cognitive therapy in people with depression distinguished by the presence or absence of personality disorder. Method: Random assignment of 180 out-patients with depression to 16 weeks of antidepressant medication or cognitive therapy. Random assignment of medication responders to continued medication or placebo, and comparison with cognitive therapy responders over a 12-month period. Results: Personality disorder status led to differential response at 16 weeks; 66% v. 44% (antidepressants v. cognitive therapy respectively) for people with personality disorder, and 49% v. 70% (antidepressants v. cognitive therapy respectively) for people without personality disorder. For people with personality disorder, sustained response rates over the 12-month follow-up were nearly identical (38%) in the prior cognitive therapy and continuation-medication treatment arms. People with personality disorder withdrawn from medication evidenced the lowest sustained response rate (6%). Despite the poor response of people with personality disorder to cognitive therapy, nearly all those who did respond sustained their response. Conclusions: Comorbid personality disorder was associated with differential initial response rates and sustained response rates for two well-validated treatments for depression. Declaration of interest: R.C.S has received grant support from GlaxoSmithKline Pharmaceuticals. Funding detailed in Acknowledgements.