Introduction: This is the first large randomized-controlled trial to evaluate whether commercially available VR hardware and software can be used for exposure therapy. The aim of this study was to compare gold-standard One Session Therapy (OST) for reduction of spider phobia symptoms and avoidance behavior using in vivo spiders and a human therapist, to a newly developed single-session gamified Virtual Reality Exposure Therapy (VRET) application with modern, consumer-available VR hardware, virtual spiders, and a virtual therapist. Method: Subjects (N=100) with spider phobia, diagnosed, and meeting inclusion criteria were recruited from the general population and randomized to 2 treatment arms. In 1-week intervals, pre-measurement, 3-hr treatment and post-measurement were completed with an in-vivo behavioral approach test (BAT) serving as the primary outcome measure for both groups. This study was powered to detect a non-inferiority margin of a 2-point between-group difference on the BAT, with a standard deviation of 4 (at 80% power). Results: 98 patients commenced treatment and 97 patients completed post-measurement. Per protocol analysis indicated VR was not non-inferior to OST. Repeated-measures ANOVA identified a significant main effect of time.