Orbitofrontal cortex (OFC) is classically linked to inhibitory control, emotion regulation and reward processing. Recent perspectives propose that the OFC also generates predictions about perceptual events, actions, and their outcomes. We tested the causal involvement of the OFC in detecting violations of prediction at two levels of abstraction (i.e., hierarchical predictive processing) by studying the event-related potentials (ERPs) of patients with focal OFC lesions (n = 12) and healthy controls (n = 14) while they detected deviant sequences of tones in a Local-Global paradigm. The structural regularities of the tones were controlled at two hierarchical levels by rules defined at a local (i.e., between tones within sequences) and at a global (i.e., between sequences) level. In OFC patients, ERPs elicited by standard tones were unaffected at both local and global levels compared to controls. However, patients showed an attenuated mismatch negativity (MMN) to local prediction violation, as well as a diminished and delayed MMN/P3a complex to the combined local and global level prediction violation. Importantly, the subsequent P3b component to conditions involving violations of prediction at the level of global rules was preserved in the OFC group. The altered magnitudes and time courses of MMN/P3a responses after lesions to the OFC indicate fundamental impairments in detecting violation of auditory regularity at two hierarchical levels of stimuli abstraction.