The ability to respond to unexpected stimuli (the 'orienting response') is a fundamental characteristic of mammalian behaviour, but the brain mechanisms by which novelty is detected remain poorly defined. Electrophysiological recordings of scalp and intracranial event-related potentials (ERPs) have shown that novel stimuli activate a distributed network involving prefrontal and posterior association cortex. In addition, ERP and single-neuron recordings, as well as neuroimaging and modelling studies, have suggested that temporal cortical regions, including the hippocampus, are also involved. To examine further the role of the medial temporal lobe in novelty processing, I measured physiological responses to novel auditory and tactile stimuli in patients with damage to the posterior hippocampal region. In normal control subjects, unexpected novel stimuli produce a characteristic ERP signal, accompanied by an autonomic skin response. Both responses are reduced in hippocampal lesion patients, whereas the response to expected control stimuli is unaffected. Thus the hippocampal region, in addition to its known role in memory formation, is an essential component of the distributed limbic-cortical network that detects and responds to novel stimuli.