Different lines of evidence have suggested an involvement of the insular cortex in pain processing. Direct electrical stimulation (ES) of the human insular cortex during surgical procedure sometimes induces painful sensations and painful stimuli induce activation of the insular cortex as shown by functional neuroimaging. Invasive evaluation of epileptic patients by deep brain stereotactically implanted electrodes provides an opportunity to analyze responses induced by ES of the insular cortex in awake and fully conscious patients. For this study, we included 25 patients suffering from drug refractory focal epilepsy with at least one electrode stereotactically implanted in the insular cortex using an oblique approach (transfrontal or transparietal). Out of the 83 responses induced by insular ES, eight (9.6%) were reported by five patients as painful sensations. Four were restricted to the cephalic region and four were felt on the ipsilateral or bilateral upper limbs, the shoulders and the trunk (pinprick sensations). The eight stimulation sites were anatomically localized via image fusion between pre-implantation 3D MRI and post-implantation 3D CT scans revealing the electrode contacts. All sites inducing painful sensations were restricted to the upper portion of the middle short gyrus of the insula. The findings of this study suggest that middle short gyrus is involved in the processing of pain-producing stimuli.