The subjective experience of pain is influenced by interactions between prior experiences, future predictions and incoming afferent information. Expectations of high pain can exacerbate pain while expectations of low pain during a consistently noxious stimulus can produce significant reductions in pain. However, the brain mechanisms associated with processing mismatches between expected and experienced pain are poorly understood, but are important for imparting salience to a sensory event in order to override erroneous top-down expectancy-mediated information. The present investigation examined pain-related brain activation when expectations of pain were abruptly violated. After conditioning participants to cues predicting low or high pain, ten incorrectly cued stimuli were administered across 56 stimulus trials to determine if expectations would be less influential on pain when there is a high discordance between pre-stimulus cues and corresponding thermal stimulation. Incorrectly cued stimuli produced pain ratings and pain-related brain activation consistent with placebo analgesia, nocebo hyperalgesia, and violated expectations. Violated expectations of pain were associated with activation in distinct regions of the inferior parietal lobe, including the supramarginal and angular gyrus, and intraparietal sulcus, the superior parietal lobe, cerebellum and occipital lobe. Thus, violated expectations of pain engage mechanisms supporting salience-driven sensory discrimination, working memory, and associative learning processes. By overriding the influence of expectations on pain, these brain mechanisms are likely engaged in clinical situations where patients’ unrealistic expectations for pain relief diminish the efficacy of pain treatments. Accordingly, these findings underscore the importance of maintaining realistic expectations to augment the effectiveness of pain management.