The prefrontal cortex (PFC) receives substantial anatomical input from the amygdala, and these two structures have long been implicated in reward-related learning and decision making. Yet little is known about how these regions interact, especially in humans. We investigated the contribution of the amygdala to reward-related signals in PFC by scanning two rare subjects with focal bilateral amygdala lesions using fMRI. The subjects performed a reversal learning task in which they first had to learn which of two choices was the more rewarding, and then flexibly switch their choices when contingencies changed. Compared with healthy controls, both amygdala lesion subjects showed a profound change in ventromedial prefrontal cortex (vmPFC) activity associated with reward expectation and behavioral choice. These findings support a critical role for the human amygdala in establishing expected reward representations in PFC, which in turn may be used to guide behavioral choice.