Importance: Globally, access to evidence-based psychological treatment is limited. Innovative self-help methods using smartphone applications and low-cost virtual reality have the potential to significantly improve the accessibility and scalability of psychological treatments. Objective: To examine the effectiveness of ZeroPhobia, a fully self-guided app-based virtual reality cognitive behavior therapy (VR CBT) using low-cost (cardboard) virtual reality goggles compared with a wait-list control group and to determine its user friendliness. Design, Setting, and Participants: In a single-blind randomized clinical trial, participants were enrolled between March 24 and September 28, 2017, and randomly assigned (1:1) by an independent researcher to either VR CBT app or a wait-list control group. A total of 193 individuals aged 18 to 65 years from the Dutch general population with acrophobia symptoms and access to an Android smartphone participated. The 6 animated modules of the VR-CBT app and gamified virtual reality environments were delivered over a 3-week period in participants' natural environment. Assessments were completed at baseline, immediately after treatment, and at 3-month follow-up. Analysis began April 6, 2018, and was intention to treat. Intervention: Self-guided app-based VR CBT. Main Outcomes and Measures: The primary outcome measure was the Acrophobia Questionnaire. The hypothesis was formulated prior to data collection. Results: In total, 193 participants (129 women [66.84%]; mean [SD] age, 41.33 [13.64] years) were randomly assigned to intervention (n = 96) or a wait-list control group (n = 97). An intent-to-treat analysis showed a significant reduction of acrophobia symptoms at posttest at 3 months for the VR-CBT app compared with the controls (b = -26.73 [95% CI, -32.12 to -21.34]; P < .001; d = 1.14 [95% CI, 0.84 to 1.44]). The number needed to treat was 1.7. Sensitivity and robustness analysis confirmed these findings. Pretreatment attrition was 22 of 96 (23%) because of smartphone incompatibility. Of the 74 participants who started using the VR-CBT app, 57 (77%) completed the intervention fully. Conclusions and Relevance: A low-cost fully self-guided app-based virtual reality cognitive behavioral therapy with rudimentary virtual reality goggles can produce large acrophobia symptom reductions. To our knowledge, this study is the first to show that virtual reality acrophobia treatment can be done at home without the intervention of a therapist. Trial Registration: Trialregister.nl identifier: NTR6442.