Learning occurs when an outcome deviates from expectation (prediction error). According to formal learning theory, the defining paradigm demonstrating the role of prediction errors in learning is the blocking test. Here, a novel stimulus is blocked from learning when it is associated with a fully predicted outcome, presumably because the occurrence of the outcome fails to produce a prediction error. We investigated the role of prediction errors in human reward-directed learning using a blocking paradigm and measured brain activation with functional magnetic resonance imaging. Participants showed blocking of behavioral learning with juice rewards as predicted by learning theory. The medial orbitofrontal cortex and the ventral putamen showed significantly lower responses to blocked, compared with nonblocked, reward-predicting stimuli. In reward-predicting control situations, deactivation in orbitofrontal cortex and ventral putamen occurred at the time of unpredicted reward omissions. Responses in discrete parts of orbitofrontal cortex correlated with the degree of behavioral learning during, and after, the learning phase. These data suggest that learning in primary reward structures in the human brain correlates with prediction errors in a manner that complies with principles of formal learning theory.