Right-handed subjects tend to respond faster to stimuli presented in the visual hemifield that spatially corresponds to the responding hand. In a typical Simon task, response is based on a non-spatial salient feature of the stimulus (e.g. color) whereas its position must be ignored. However, the spatial position of the stimulus interferes with the processing of the salient characteristic. Subjects are significantly faster when stimulus side and response side correspond (corresponding condition) than when they do not (non-corresponding condition). We have previously shown with behavioral experiments that, when subjects practice reversed contingencies (that is, spatially incompatible trials) in a session preceding the Simon task, they show a long-term retention of these associations, resulting in the disappearance of the latency cost typically observed in non-corresponding trials. Here we show, by means of the lateralized readiness potential, that the neural correlate of such behavioral plasticity is an increase in premotor cortex activation during preparation of non-corresponding responses. This effect showed a marked left-right asymmetry which suggests an important role of subjects' handedness. Our results demonstrate that humans can learn in a single session to reverse relatively stable stimulus-response associations. NeuroReport 12:973-977 (C) 2001 Lippincott Williams & Wilkins.