There is a lack of prospective studies that test pre-specified hypotheses on the role of personality traits in outpatient psychotherapy. A total of 47 patients with a broad range of psychopathological syndromes were enrolled in a prospective 6month observational study conducted in Zurich, Switzerland. We found evidence for remarkably high differential stability in all Big Five personality traits during the first 6 months of psychotherapy. Mean-level stability was very high in agreeableness and conscientiousness, while modest changes were observed in neuroticism, extraversion and openness. Baseline scores in neuroticism and conscientiousness at the beginning of therapy predicted modest change in self-reported severity of psychopathology over 6 months, but no effect was found in association with therapist-rated functional deficits. We conclude that personality trait levels may change slightly over the course of 6 months of psychotherapy and that both neuroticism and conscientiousness may have weak associations with the self-perceived improvement in psychopathology.