Behavioral studies using motor preparation paradigms have revealed that increased expectancy of a response signal shortens reaction times (RTs). Neurophysiological data suggest that in such paradigms, not only RT but also neuronal activity in the motor structures involved is modulated by expectancy of behaviorally relevant events. Here, we directly tested whether expectancy of a response signal modulates excitability of the corticospinal system used in the subsequent movement. We combined single- and paired-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex with a simple RT task with variable preparatory delays. We found that, in line with typical behavioral observations, the subjects' RTs decreased with increasing response signal expectancy. TMS results revealed a modulation of corticospinal excitability in correspondence with response signal expectancy. Besides an increased excitability over the time-course of the preparatory delay, corticospinal excitability transiently increased whenever a response signal was expected. Paired-pulse TMS showed that this modulation is unlikely to be mediated by excitability changes in interneuronal inhibitory or facilitatory networks in the primary motor cortex. Changes in corticospinal synchronization or other mechanisms involving spinal circuits are candidates mediating the modulation of corticospinal excitability by expectancy.