BACKGROUND: Venipuncture is one of the most painful and distressing procedure experienced by pediatric patients. Evidence suggests that distraction combined with age-appropriate procedural information can effectively decrease procedural pain and anxiety in pediatric patients. Immersive virtual reality (IVR) can simultaneously provide complete distraction and procedural information to patients. METHODS: Guided by the gate control theory and Lazarus and Folkman's theory, this study aims to examine the effects of IVR intervention on reducing the pain, anxiety and stress, the duration of venipuncture, and the satisfaction of healthcare providers for the procedure. A randomized controlled trial with repeated assessments will be conducted. A total of 200 pediatric patients aged 4-12 years will be recruited from a regional public hospital and randomly assigned to either the intervention or control group. The study will use two age-appropriate IVR modules that consist of procedural information. The intervention group will receive IVR intervention, whereas the control group will receive standard care only. The cost-effectiveness of IVR intervention will be compared with that of standard care. Outcome evaluation will be conducted at four time points: 10 min before, during, immediately after, and 30 min after the procedure. Intention to treat and generalized estimating equation model will be used to analyze the data. DISCUSSION: This study is the first of its kind to adopt IVR intervention with age-appropriate procedural information for pediatric patients undergoing venipuncture. Findings of the proposed study may: (1) provide a novel, facile, and cost-effective intervention that can be used virtually at any time and place to manage pain and anxiety; and (2) shed light on the global trends of research and clinical development of IVR as an intervention for other painful and stressful medical procedures. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800018817 . Registered on 11 October 2018.