BACKGROUND: It has never been investigated whether comorbid personality disorder or neuroticism predicts a poor treatment outcome in first episode depression. METHODS: Medically treated patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. The patients participated in an extensive interview including the Schedules for Clinical Assessment in Neuropsychiatry, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders and a detailed assessment of medical treatment history using standardised procedures (Treatment Response to Antidepressants Questionnaire, TRAQ). Remission was defined as a score of < or =7 on the Hamilton Depression Rating Scale, 17 items, and a score of > or =4 on the TRAQ following (1) a first adequate trial of antidepressant treatment, and (2) 2 trials of antidepressant treatment. Further personality traits were assessed by means of the Eysenck Personality Questionnaire. RESULTS: Among a total of 301 patients with a single depressive episode, 31.9% fulfilled diagnostic criteria for at least 1 personality disorder of any kind. Comorbid personality disorder was associated with a 2.2-times (95% CI: 1.1-4.2) increased risk of non-remission following the first antidepressant trial, whereas no effect was found following the second antidepressant trial (OR: 1.6; 95% CI: 0.8-3.4). A high level of neuroticism was associated with non-remission in first as well as second trials. CONCLUSION: Comorbid personality disorder and high levels of neuroticism in first episode depression predict an increased risk of non-remission from depression.