Summary: During operative intervention for the treatment of symptomatic neuromas, the authors have observed a hypersensitive “startle” response to stimulation in proximity to the painful nerve. This physiologic sign is an indicator of the specific anatomic localization of the painful stimulus, commonly a symptomatic neuroma, that appears to be reproducible. The aim of this article is to describe this “neuroma startle sign,” posit the underlying mechanism for this observation, and propose how this phenomenon could be clinically harnessed for innovation and optimization in both surgery and anesthesia for more effective symptomatic neuroma localization.