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Abstract Overdoses from non-medical use of opioids can lead to hypoxemic/hypercarbic respiratory failure, cardiac arrest, and death when left untreated. Opioid toxicity is readily reversed with naloxone, a competitive antagonist that can restore respiration. However, there remains a critical need for technologies to administer naloxone in the event of unwitnessed overdose events. We report a closed-loop wearable injector system that measures respiration and apneic motion associated with an opioid overdose event using a pair of on-body accelerometers, and administers naloxone subcutaneously upon detection of an apnea. Our proof-of-concept system has been evaluated in two environments: (i) an approved supervised injection facility (SIF) where people self-inject opioids under medical supervision and (ii) a hospital environment where we simulate opioid-induced apneas in healthy participants. In the SIF (n= 25), our system identified breathing rate and post-injection respiratory depression accurately when compared to a respiratory belt. In the hospital, our algorithm identified simulated apneic events and successfully injected participants with 1.2 mg of naloxone. Naloxone delivery was verified by intravenous blood draw post-injection for all participants. A closed-loop naloxone injector system has the potential to complement existing evidence-based harm reduction strategies and, in the absence of bystanders, help make opioid toxicity events functionally witnessed and in turn more likely to be successfully resuscitated.