T imbre is an important factor that affects the perception of emotion in music. To date, little is known about the effects of timbre on neural responses to musical emotion. To address this issue, we used ERPs to investigate whether there are different neural responses to musical emotion when the same melodies are presented in different timbres. With a cross-modal affective priming paradigm, target faces were primed by affectively congruent or incongruent melodies without lyrics presented in the violin, flute, and voice. Results showed a larger P3 and a larger left anterior distributed LPC in response to affectively incongruent versus congruent trials in the voice version. For the flute version, however, only the LPC effect was found, which was distributed over centro-parietal electrodes. Unlike the voice and flute versions, an N400 effect was observed in the violin version. These findings revealed different patterns of neural responses to musical emotion when the same melodies were presented in different timbres, and provide evidence for the hypothesis that there are specialized neural responses to the human voice.