Pre-attentive registration of aberrations in predictable sound patterns is attributed to the temporal cortex. However, electrophysiology suggests that frontal areas become more important when deviance complexity increases. To play an instrument in an ensemble, professional musicians have to rely on the ability to detect even slight deviances from expected musical patterns and therefore have highly trained aural skills. Here, we aimed to identify the neural correlates of experience-driven plasticity related to the processing of complex sound features. We used functional magnetic resonance imaging in combination with an event-related oddball paradigm and compared brain activity in professional musicians and non-musicians during pre-attentive processing of melodic contour variations. The melodic pattern consisted of a sequence of five tones each lasting 50 ms interrupted by silent interstimulus intervals of 50 ms. Compared to non-musicians, the professional musicians showed enhanced activity in the left middle and superior temporal gyri, the left inferior frontal gyrus and in the right ventromedial prefrontal cortex in response to pattern deviation. This differential brain activity pattern was correlated with behaviorally tested musical aptitude. Our results thus support an experience-related role of the left temporal cortex in fast melodic contour processing and suggest involvement of the prefrontal cortex. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc.