Action observation enhances cortico-spinal excitability. Here we tested the specificity of this effect and the role played by the orientation of the observer. Ten normal subjects observed video clips of right hand performing three different finger movements (thumb ab-/adduction, index ab-/adduction, index extens-/flexion) in two different orientations (Away, i.e., natural hand-orientation facing out from the observer; or Toward, i.e., unnatural hand-orientation facing toward the observer). Motor-evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) were recorded from the abductor pollicis brevis (APB) and the first dorsal interosseus (FDI) muscles. Movement direction of the index finger was recorded using force transducers. Facilitation of MEP size was significantly greater for APB during observation of thumb movements and for FDI during observation of index finger movements. Facilitation of MEP size was significantly greater when the hand presented on screen was facing out from and corresponding to that of the observer (Away orientation). The direction of the index finger movement evoked by TMS shifted toward extension/flexion versus ab-/adduction matching the observed movement. Our results give further evidence that observation of a movement enhances motor output to the muscles involved in the movement and facilitates the observed action. In addition, we provide novel evidence about the high degree of specificity of this observation-induced motor cortical modulation. The degree of modulation depends on hand orientation. The modulation is maximal when the observed action corresponds to the orientation of the observer.