Objective: This study compared the efficacy of a technician-assisted single-session virtual reality exposure therapy (VRET)for the treatment of spider phobia featuring low-cost consumer-available hardware and novel automated software to gold-standard in-vivo one-session treatment (OST), using a parallel group randomized non-inferiority design. Method Participants (N = 100)were randomized to VRET and OST arms. Assessors blinded to treatment allocation evaluated participants at pre- and post-treatment as well follow-up (3 and 12 months)using a behavioral approach test (BAT)and self-rated fear of spider, anxiety, depression and quality-of-life scales. A maximum post-treatment difference of 2-points on the BAT qualified as non-inferiority margin. Results Linear mixed models noted large, significant reductions in behavioral avoidance and self-reported fear in both groups at post-treatment, with VRET approaching the strong treatment benefits of OST over time. Non-inferiority was identified at 3- and 12- months follow-up but was significantly worse until 12-months. There was no significant difference on a questionnaire measuring negative effects. Conclusions Automated VRET efficaciously reduced spider phobia symptoms in the short-term and was non-inferior to in-vivo exposure therapy in the long-term. VRET effectiveness trials are warranted to evaluate real-world benefits and non-specific therapeutic factors accruing from the presence of a technician during treatment. ClinicalTrials.gov (NCT02533310).