This study analysed the time course of neuro-mechanical changes underlying stretch-shortening cycle during intermittent exhaustive rebound exercise. On a sledge apparatus, ten subjects repeated until exhaustion a series of 30 unilateral submaximal rebounds, with intermediate 3-min rest periods. Rebound height, ground reaction force, 3D tibial acceleration and electromyographic activity of major lower limb muscles were recorded. A maximal drop jump test performed before and after the exhaustive exercise revealed a 10% drop in maximal stretch-shortening cycle (SSC) performance. Specific investigation of the neuro-mechanical changes along the exhaustive exercise included classical comparison of the first (BEG) and last (END) rebound series. From the initial accommodation phase, an optimized (OPTIM) series was individually determined as the first of at least two subsequent series with significantly shorter contact time than in the BEG series. The OPTIM series was reached after 3 +/- 1 series, with associated increased lower limb stiffness during the braking phase and decreased muscle activities during the push-off. The major result was that the early (BEG-OPTIM) changes explained most of the BEG-END ones whereas the actual (OPTIM-END) fatigue effects remained quite limited. This confirmed our expectation that erroneous quantification of the SSC fatigue effects might be drawn when using the early beginning of rebound exercise on the sledge as a reference. Actual fatigue effects included medio-lateral instability as suggested by increased peroneus longus preactivation and medio-lateral tibial acceleration. The present methodology is thus considered as improving the distinction between SSC optimization and its deterioration with fatigue.