BACKGROUND: Chronic pain in adolescents is a significant and growing concern, as it can have negative implications on physical and psychosocial development. Management can be complicated by the increasing risks associated with opioid misuse, highlighting the need for effective nonpharmacological interventions. Biofeedback is an empirically supported behavioral intervention for chronic pain that targets the self-regulation of physiological responses. Virtual reality (VR) is a novel delivery method for biofeedback that could serve as an engaging and effective platform for adolescents. OBJECTIVE: The goal of this study was to assess the feasibility, acceptability, and preliminary effectiveness of integrating a VR-delivered respiratory biofeedback intervention into an outpatient pediatric pain rehabilitation program (PPRP) for adolescents with chronic pain. METHODS: In this pilot study, we recruited 9 participants from those enrolled in the PPRP at Nemours Children's Hospital. Participants underwent 2 VR respiratory biofeedback sessions per week over a 4-week period using AppliedVR's "RelieVRx" program. Feasibility was defined as >60% of eligible patients enrolling with at least 80% of VR sessions completed. Acceptability was assessed via validated acceptability questionnaires, with high acceptability defined as an average acceptability rating score >3 on a 5-point Likert scale. Open-ended responses were analyzed via qualitative analysis. Preliminary effectiveness was assessed with questionnaires measuring the quality of life (Pediatric Quality of Life Inventory [PedsQL]) and level of pain interference in daily activities (Functional Disability Inventory) before and after participation in the pain program. Finally, heart rate (HR) and blood pressure (BP) were measured before and after each VR session. RESULTS: Of 14 eligible PPRP patients, 9 (64%) enrolled in the VR respiratory biofeedback study, and 7 (77% of study participants) completed at least 80% of biofeedback sessions. Participants reported high acceptability with average session ratings ranging from 3.89 to 4.16 on post-VR program questionnaires. Of 224 open-ended responses, participants reported changes in stress and somatic symptoms (ie, pain distraction and breathing regulation). There was a statistically significant increase in the average physical functioning score of the PedsQL among participants (P=.01) from pre- to postparticipation in the overall pain program. The cohort's average emotional functioning score of the PedsQL also increased, though this change was not statistically significant (P=.17). Participants' Functional Disability Inventory scores significantly decreased from an average of 25.1 to 11 from before to after the pain program (P=.002). There were no significant differences between pre- versus post-BP or HR for any session. However, decreased BP and HR were observed across most sessions. CONCLUSIONS: AppliedVR respiratory biofeedback demonstrated initial feasibility, acceptability, and preliminary effectiveness when implemented as part of a PRPP. This study underscores the need for future larger-scale studies analyzing the use of VR biofeedback in adolescent populations with chronic pain.