IMPORTANCE Multidisciplinary prehabilitation before total knee replacement (TKR) for osteoarthritis may improve outcomes in the postoperative period. OBJECTIVE To compare multidisciplinary prehabilitation with usual care before TKR for osteoarthritis in terms of functional independence and activity limitations after surgery. DESIGN, SETTING, AND PARTICIPANTS This prospective, open-label randomized clinical trial recruited participants 50 to 85 years of age with knee osteoarthritis according to the American College of Rheumatology criteria for whom a TKR was scheduled at 3 French tertiary care centers. Recruitment started on October 4, 2012, with follow-up completed on November 29, 2017. Statistical analyses were conducted from March 29, 2018, to March 6, 2019. INTERVENTIONS Four supervised sessions of multidisciplinary rehabilitation and education (2 sessions per week, at least 2 months before TKR, delivered to groups of 4-6 participants at each investigating center; session duration was 90 minutes and included 30 minutes of education followed by 60 minutes of exercise therapy) or usual care (information booklet and standard advice by the orthopedic surgeon) before TKR. MAIN OUTCOMES AND MEASURES The short-term primary end point was the proportion of participants achieving functional independence a mean (SD) of 4 (1)days after surgery defined as level 3 on the 4 functional tests. The midterm primary end point was activity limitations within 6 months after TKR assessed by the area under the receiver operating characteristic curve of the self-administered Western Ontario Questionnaire and McMaster Universities Osteoarthritis Index function subscale. RESULTS A total of 262 patients (mean [SD] age, 68.6 [8.0] years; 178 women [68%)) were randomized (131 to each group). A mean (SD) of 4 (1) days after surgery, 34 of 101(34%) in the experimental group vs 26 of 95 (27%) in the control group achieved functional independence (risk ratio, 1.4; 97.5% CI, 0.9-2.1; P = .15). At 6 months, the mean (SD) area under the curve for the Western Ontario Questionnaire and McMaster Universities Osteoarthritis Index function subscale was 38.1 (16.5) mm(2) in the experimental group vs 40.6 (17.8) mm(2) in the control group (absolute difference, -2.8 mm(2); 97.5% CI, -7.8 to 2.3; P = .31 after multiple imputation). No differences were found in secondary outcomes. CONCLUSIONS AND RELEVANCE This randomized clinical trial found no evidence that multidisciplinary prehabilitation before TKR for osteoarthritis improves short-term functional independence or reduces midterm activity limitations after surgery.