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Objective: Oxytocin (OT) synchrony has been suggested as a key mechanism by which bonds are formed and strengthened in various species, including those between mother and infant and between romantic partners. It is unknown whether such biological synchrony also plays a role in psychotherapy efficacy, where it may underlie the adverse effect of social impairment on the efficacy of treatment of depression. Method: Five hundred eighty OT saliva samples were collected from 37 patient–therapist dyads on a fixed schedule over a 16-session ongoing randomized controlled trial for psychotherapy for depression. Biological synchrony was operationalized as the correlation between changes occurring repeatedly over treatment in patient and therapist OT levels pre- to postsession. Results: OT synchrony between patients and therapists was found to be associated with effective treatment. The findings support the proposed mediation model: (a) poorer social functioning at baseline predicted lower levels of patient–therapist synchrony in OT changes from pre- to postsession over the course of treatment; (b) lower levels of therapist–patient OT synchrony, in turn, predicted less reduction in depressive symptoms during treatment; and (c) based on quasi-Bayesian Monte Carlo simulations, the levels of therapist–patient synchrony significantly mediated the association between social impairment and reduction in depressive symptoms. Findings were replicated using robust inferential methods. Conclusions: The findings suggest that OT synchrony between patient and therapist may be a biological mechanism by which impaired interpersonal functioning undermines treatment outcome. What is the public health significance of this article?: To our knowledge, this is the first study to focus on the biological synchrony between patients and their therapists during treatment sessions and to suggest that this synchrony is an important mechanism underlying the effects of impaired interpersonal functioning on treatment outcome. Patients with poorer social functioning at baseline were less biologically synchronized with their therapists during treatment sessions, and the poorer synchrony was associated with lower ability to benefit from treatment and to achieve symptoms reduction. [ABSTRACT FROM AUTHOR]