Background: The impact of personality dysfunction on the outcome of treatment for depression remains debated. Aims: To examine the relationship between the number of prior depressive episodes, personality dysfunction and treatment response for depression. Method: In a large sample (n=8229) of adult out-patients with a major depressive episode (DSM-IV), personality dysfunction was assessed using the Standardised Assessment of Personality - Abbreviated Scale (SAPAS). Potential predictors of treatment response at 6 weeks were examined via structural equation modelling. Results: The amount of personality dysfunction and number of prior episodes of depression were both associated with poor response to treatment. Once personality dysfunction was controlled for, the number of prior episodes of depression was not associated with treatment response. Conclusions: Personality dysfunction is associated with impaired short-term response to antidepressant treatment in major depression. The apparent detrimental effect of prior depression on treatment response may be accounted for by pre-existing personality dysfunction.