Background: The prevention of care-induced pain is a central concern for all healthcare teams in hematology units. Use of MEOPA (Oxygen + Nitrous Oxide) is today a standard of care for relaxation procedure. Distraction through immersion in virtual reality (VR) has already documented its analgesic effects in several phase II trials but comparison with standard treatments in a large randomized study is needed. Methods: We conducted an open-label multicenter randomized phase III trial (ClinicalTrials.gov identifier: NCT03483194). We assessed the safety and efficacy of a new therapeutic virtual reality solution for pain distraction, Bliss, in prevention of pain and anxiety before performing a bone marrow biopsy. Bliss is a VR software with four imaginary interactive environments in three dimensions with binaural sound (head-mounted display). Efficacy was evaluated by pain intensity with visual analog scale (score from 0 to 10) just after the biopsy and anxiety by 2 questionnaires (fear of pain before the biopsy and revised STAI questionnaire before and after the biopsy). The primary end point was patient-assessed pain intensity after the bone marrow procedure. Results: A total of 126 patients were enrolled with previously untreated malignant hemopathy between September 6, 2018 and May 18, 2020. They were randomly assigned in a 1:1 ratio to receive pain prevention with MEOPA (n=63) or Bliss (n=63) before and during their bone marrow biopsy. All patients received a local anesthesia with lidocaïne before the biopsy. Median age of the study population was 65.5 years old (range 18 to 87) and 54,2% were men. The average pain intensity was 3.5 (standard deviation 2.6) for the MEOPA group and 3.0 (SD 2.4) for the VR group (p=0,26) without any significant difference according to age, gender or hemopathy. Concerning anxiety, 67.5% of patients were afraid before the biopsy and anxiety scores were moderate to very high in 26.3% of patients before the biopsy (STAI questionnaire) and 9.0% after the biopsy for all patients (17.3% of reduction in anxiety for the MEOPA group and 17.2% for the VR group, p=0.83). Immersion in VR was well tolerated in 100% of patients included in the VR group. Physicans were very satisfied by the relaxation procedure in 64.9% of cases (52.5% in the MEOPA group and 77.6% in the VR group, p=0.01) and recommended re-use of the technique in 54.2% in the MEOPA group and 79,1% in the VR group (p=0.02). Conclusion: The intensity of pain did not significantly differ in both arms. Bliss-based relaxation method was well tolerated and the satisfaction of patients and physicians was very high in VR group. This study validates the use of immersion in VR with Bliss as a new digital therapeutics and support the integration of the software in the panel of supportive care. Key words: virtual reality, bone marrow biopsy, pain. Clinical trial information: 03483194.