Substance use disorders (SUDs) are a significant public health concern, with over 30% failing available treatment. Severe SUD is characterized by drug-cue reactivity that predicts treatment-failure. We leveraged this pathophysiological feature to personalize deep brain stimulation (DBS) of the nucleus accumbens region (NAc) in an SUD patient. While this DBS lead was externalized for clinical purposes, we administered a personalized drug cue-reactivity task while recording NAc electrophysiology. We identified a cue-evoked signal in the ventral NAc associated with intensification of opioid-related cravings, which attenuated with therapeutic stimulation delivered to this same area. DBS was then programmed to engage this subregion within NAc to account for the biomarker location, heralding the potential for personalized strategies to optimize DBS for SUD.