We analyzed the only two sudden unexpected death in epilepsy (SUDEP) cases from 320 prospectively recruited patients in the three-year Prevention and Risk Identification of SUDEP Mortality (PRISM) Project. Both patients had surgically refractory epilepsy, evidence of left insular damage following previous temporal/temporo-insular resections, and progressive changes in Heart Rate Variability (HRV) in monitored evaluations prior to death. Insular damage is known to cause autonomic dysfunction and increased mortality in acute stroke. This report suggests a possible role for the insula in the pathogenesis of SUDEP. The presence of intrinsic insular lesions or acquired insular damage in refractory epilepsy patients may be an additional risk factor for SUDEP.