A large body of evidence has shown that musicians’ brains differ in many ways from nonmusicians’ brains due to the particularly intense and prolonged sensorimotor training involved. Not much is known about the effects of the specific musical instrument played on brain processing of audiovisual information. In this study the effect of musical expertise was investigated in professional clarinetists and violinists. One hundred and eighty videos showing fragments of musical performances played on a violin or a clarinet were presented to musicians of G. Verdi Milan Conservatory and age-matched controls. Half of the musicians were violinists, the other half were clarinetists; event-related potentials (ERPs) were recorded from 128 scalp sites and analyzed. Participants judged how many notes were played in each clip. The task was extremely easy for all participants. Over prefrontal areas an anterior negativity response was found to be much larger in controls than in musicians, and in musicians for the unfamiliar over the familiar musical instrument. Furthermore, a later central negativity response showed a lack of note numerosity effect in the brains of musicians for their own instrument, but not for unfamiliar instrument. The data indicate that music training is instrument-specific and that it profoundly affects prefrontal encoding of music-related information and auditory processing.