Depression is associated with reduced quality of life (QoL), and personality pathology is associated with higher impairment and poorer treatment outcomes in patients with depression. This study aims to analyze the effects of personality functioning on the QoL of patients with depression. Severity of depressive symptoms (Beck Depression Inventory), level of personality functioning (Operationalized Psychodynamic Diagnosis Structure Questionnaire), and QoL (Medical Outcome Study 36-item Short-Form) were assessed in a sample of 84 depressive outpatients. Personality functioning showed main effects on both the mental and physical components of QoL. A moderating effect of personality functioning on the relationship between depressive symptoms and QoL was tested but not confirmed. Severity of depressive symptoms was found to mediate the effect of personality functioning on the mental component of QoL. These results suggest that the effect of personality functioning on the QoL of patients with depression may be related to the higher severity of depressive symptoms found in patients with lower levels of personality functioning.