Abstract Background Femorotibial knee osteoarthritis is associated with muscle weakness in the lower limbs, particularly in the quadriceps, which results in disease progression. The interest of having muscular strengthening as part of the therapeutic arsenal for the medical treatment of knee osteoarthritis is now well established. The functional disability induced by knee osteoarthritis manifests itself principally when walking, notably downhill, during which the muscles are called upon to contract eccentrically. We can therefore think that eccentric muscular strengthening could bring a functional benefit that is superior to concentric muscular strengthening. Methods/Design This is a prospective, randomized, bicenter, parallel-group, international study. Eighty patients aged from 40 to 75 years old, suffering from medical-stage knee osteoarthritis, will undertake 6 weeks of isokinetic muscular strengthening. Randomization determines the mode of muscular strengthening: either exclusively eccentric or exclusively concentric. The principal objective is to demonstrate the superiority of the improvement in the quadriceps isokinetic torque after isokinetic muscular strengthening by the eccentric mode compared to the concentric mode. The following parameters are also evaluated: the variations in the level of pain, the parameters of walking (maximum speed over 10 and 200 meters, analysis on a computerized Gaitrite™ treadmill), static equilibrium (on a FUSYO™ force platform), and the functional status of the patient using the Western Ontario and MacMaster Universities osteoarthritis index (WOMAC) questionnaire after the strengthening period and at 6 months. Discussion A better knowledge of the most effective mode of muscular strengthening is needed to optimize the functional benefits to the patients. In case of superiority in terms of efficacy of the eccentric mode, the latter could be given priority in the rehabilitation treatment of knee osteoarthritis patients. Trial registration Clinical trials.gov number: NCT01586130.