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This review aims to provide a framework for evaluating the utility of virtual reality (VR) as a distraction intervention to alleviate pain and distress during medical procedures. We first describe the theoretical bases underlying the VR analgesic and anxiolytic effects and define the main factors contributing to its efficacy, which largely emerged from studies on healthy volunteers. Then, we provide a comprehensive overview of the clinical trials using VR distraction during different medical procedures, such as burn injury treatments, chemotherapy, surgery, dental treatment, and other diagnostic and therapeutic procedures.A broad literature search was performed using as main terms “virtual reality,” “distraction,” and “pain.” No date limit was applied and all the retrieved studies on immersive VR distraction during medical procedures were selected.VR has proven to be effective in reducing procedural pain, as almost invariably observed even in patients subjected to extremely painful procedures, such as patients with burn injuries undergoing wound care, and physical therapy. Moreover, VR seemed to decrease cancer-related symptoms in different settings, including during chemotherapy. Only mild and infrequent side effects were observed.Despite these promising results, future long-term randomized controlled trials with larger sample sizes and evaluating not only self-report measures but also physiological variables are needed. Further studies are also required both to establish predictive factors to select patients who can benefit from VR distraction and to design hardware/software systems tailored to the specific needs of different patients and able to provide the greatest distraction at the lowest cost.