Introduction.- Knee injuries are frequent in a young and active population. Most of the patients resume their professional activity but few studies were interested in factors that predict a return to work. The aim of this study is to identify these predictors from a large panel of bio-psychosocial variables. We postulated that the return to work 3 months and 2 years after discharge is mostly predicted by psychosocial variables.Patients and methods.- Prospective study, patients hospitalized for a knee injury. Variables measured: the abbreviated injury score (AIS) for the gravity of the injuries, analog visual scale for the intensity of pain, INTERMED for the bio-psychosocial complexity, SF-36 for the quality of life, HADs for the anxiety/depression symptoms and IKDC score for the knee function. Univariate logistic regressions, adjusted for age and gender, were performed in order to predict return to work.Results.- One hundred and twenty-six patients hospitalized during 8 months after the accident were included into this prospective study. A total of 73 (58%) and 75 (59%) questionnaires were available after 3 months and 2 years, respectively. The SF-36 pain was the sole predictor of return to work at 3 months (odds Ratio 1.06 [1.02-1.10], P = 0.01; for a one point increase) and 2 years (odds Ratio 1.06 [1.02-1.10], P = 0.01). At three months, other factors are SF-36 (physic sub-scale), IKDC score, the presence of a work contract and the presence of litigation. The bio-psychosocial complexity, the presence of depressive symptoms predicts the return to work at two years.Discussion.- Our working hypothesis was partially confirmed: some psychosocial factors (i.e. depressive symptoms, work contract, litigation, INTERMED) predict the return to work but the physical health and the knee function, perceived by the patient, are also correlated. Pain is the sole factor isolated at both times (i.e. 3 months and 2 years) and, consequently, appears a key element in the prediction of the return to work. Some factors are accessible to the rehabilitation program but only if an interdisciplinary approach is performed.