Background: In the context of the COVID-19 pandemic, legislations are being modified around the world to allow patients to receive mental health services through telehealth. Unfortunately, there are no large clinical trial available to reliably document the efficacy of delivering videoconferencing psychotherapy (VCP) for people with panic disorder and agoraphobia (PDA) and whether basic psychotherapeutic processes are altered. Methods: This 2-arm intent-to-treat non-inferiority study reports on a clinical trial on VCP and documents how therapeutic working alliance and motivation toward psychotherapy are associated to treatment outcome. We hypothesized that VCP would not be inferior to standard face-to-face (FF) cognitive behavior therapy for PDA. No specific hypothesis was stated to address working alliance and treatment mechanisms. VCP was compared to a gold-standard psychotherapy treatment for PDA, which was delivered either in person or in videoconference, with a strict tolerance criterion of about 2 points on the primary outcome measure. Seventy one adult patients were recruited. Measures of working alliance were collected after the first, fifth, and last session. Motivation toward therapy at pre-treatment and working alliance after the fifth therapy session were used as predictors of treatment outcome and compared with change in dysfunctional beliefs toward bodily sensations. Results: Panic disorder, agoraphobia, fear of sensations and depressed mood all showed significant improvements and large effect-sizes from pre to post-treatment. Gains were maintained at follow-up. No significant differences were found between VCP and FF, and effect sizes were trivial for three of the four outcome measures. Noninferiority tests confirmed that VCP was no less effective than FF therapy on the primary outcome measure and two of the three secondary outcome measures. Working alliance was very strong in VCP and did not statistically differ from FF. Working alliance and motivation did not predict treatment outcome, which was significantly predicted by the