Narcolepsy with cataplexy is a sleep-wake disorder caused by a loss of hypothalamic hypocretins. Here we assessed the time course of amygdala activation during aversive conditioning in unmedicated patients with narcolepsy. Unlike healthy matched control subjects, narcolepsy patients had no enhancement of amygdala response to conditioned stimuli and no increase in functional coupling between the amygdala and medial prefrontal cortex. These findings suggest that human narcolepsy is accompanied by abnormal emotional learning, and that, in line with animal data, the hypocretin system and the amygdala are involved in this process.