In the present study, the primary emotional response represented by the acoustic startle reflex was investigated in a group of six male patients, selected with lesions of the orbitofrontal cortex, and twenty matched healthy controls. Accurate neuropsychological assessment and lesion mapping showed relatively spared cognitive functioning in the patient group, most of the lesions being confined to the bilateral polar orbitofrontal cortex. Patients had significant inhibition of startle amplitude, together with a reduced self-evaluated perception of the unpleasantness of the acoustic probe stimulus. Results add to current literature on the circuit of the human startle reflex, by suggesting cortical-limbic down-regulation of the orbitofrontal cortex on the main startle pathway, probably at the level of the activating reticular system. The orbitofrontal cortex, together with the amygdala, is confirmed to represent the main center organizing both primary and secondary learned aspects of emotions.