BACKGROUND: Dynamic interpersonal therapy (DIT) is a short-term psychodynamic psychotherapy that has been shown to effectively reduce depressive symptoms in patients with major depressive disorder (MDD). In DIT, the depressive symptoms are formulated as responses to impaired mentalisation. DIT aims to alleviate depressive symptoms by improving mentalising. AIMS: This study aimed to examine the effect of DIT on improving mentalising and the mediating effect of mentalising in changes in depressive symptoms. METHODS: Outpatients received either DIT combined with antidepressant medication treatment (DIT group) or antidepressant medication treatment alone (ADM group) for 16 weeks. The Hamilton Depression Rating Scale (HAMD), Patient Health Questionnaire (PHQ) and Reflective Functioning Questionnaire (RFQ) were used. The intention-to-treat principle, mixed linear models, multiple imputation, Pearson's correlation analysis and mediation analysis were conducted. The per-protocol principle was used as sensitivity analysis. RESULTS: The DIT group had significantly lower HAMD (least-squares (LS) mean difference=-3.756, p<
0.001), PHQ (LS mean difference=-4.188, p<
0.001), uncertainty about mental states in the RFQ (RFQ-U, LS mean difference=-2.116, p<
0.001) and higher certainty about mental states in the RFQ (RFQ-C, LS mean difference=2.214, p=0.028) scores than the ADM group at post-treatment. The change in RFQ-C was marginally significantly correlated with the change in HAMD (r=-0.218, p CONCLUSIONS: The DIT group yielded better outcomes compared with the ADM group in reducing depressive symptoms and improving mentalising. Improvements in mentalising were associated with reductions in depressive symptoms. These findings support that mentalising may contribute to the therapeutic effects of DIT in MDD.