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Supplemental Digital Content is available in the text, Background: Virtual reality (VR)-based rehabilitation is a promising approach for improving recovery in many conditions to optimize functional results, enhancing the clinical and social benefits of surgery. Objective: To assess the efficacy of an early rehabilitation performed by the VR-based rehabilitation versus the traditional rehabilitation provided by physical therapists after primary total knee arthroplasty (TKA). Methods: In this randomized controlled clinical trial, 85 subjects met the inclusion criteria and were randomized 3 to 4 days after TKA to an inpatient VR-based rehabilitation and a traditional rehabilitation. Participants in both groups received 60 minutes/day sessions until discharge (around 10 days after surgery). The primary outcome was the pain intensity. The secondary outcomes were: the disability knee, the health related quality of life, the global perceived effect, the functional independent measure, the drugs assumption, the isometric strength of quadriceps and hamstrings, the flexion range of motion, and the ability to perform proprioception exercises. Outcomes were assessed at baseline (3–4 days after TKA) and at discharge. Results: VR-based or traditional rehabilitation, with 13% of dropout rate, shown no statistically significant pain reduction between groups (P = .2660) as well as in all other outcomes, whereas a statistically significant improvement was present in the global proprioception (P = .0020), in favor of the VR-based rehabilitation group. Conclusions: VR-based rehabilitation is not superior to traditional rehabilitation in terms of pain relief, drugs assumptions and other functional outcomes but seems to improve the global proprioception for patients received TKA. Level of evidence : Therapy, level 1b. CONSORT-compliant. Trial registration : http://www.clinicaltrials.gov, ClinicalTrials.gov, NCT02413996.