Placebos have been shown to induce powerful effects in a variety of medical conditions, such as pain and movement disorders, as well as to increase physical performance and endurance in healthy subjects. Here we investigated the effects of an ergogenic placebo on the performance of the quadriceps muscle, which is responsible for the extension of the leg relative to the thigh. In a first experiment, a placebo was administered along with the suggestion that it was caffeine at high dose. This resulted in a significant increase in mean muscle work across subjects, which, however, was not accompanied by a decrease of perceived muscle fatigue. In a second experiment, the placebo caffeine was administered twice in two different sessions. Each time, the weight to be lifted with the quadriceps was reduced surreptitiously so as to make the subjects believe that the ‘ergogenic agent’ was effective. After this conditioning procedure, the load was restored to the original weight, and both muscle work and perceived fatigue assessed after placebo administration. Compared with the first experiment, the placebo effect was larger, with a significant increase in muscle work and decrease in perceived muscle fatigue. Within the context of the role of peripheral and/or central mechanisms in muscle performance, the present findings suggest a central mechanism of top-down modulation of muscle fatigue. In addition, the difference between the first and second experiment underscores the role of learning in increasing muscle performance with placebos.