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Introduction: Opioid overdose rescue situations are time-critical, high-stress scenarios that frequently require nonmedical first responders or bystanders to intervene and administer naloxone to avoid opioid-induced fatalities. Training nonmedical personnel to respond during such mentally constraining situations presents the human factors challenge of how best to design a safe and effective lay delivery system. This paper comparatively evaluates the ease of use of two nasal naloxone administration products: NARCAN ® Nasal Spray and a naloxone prefilled syringe with nasal atomizer (PFS-NA)., Methods: We evaluated the use requirements and usability of NARCAN ® Nasal Spray versus a naloxone PFS-NA using a systems-oriented method. First, we determined the use requirements of different user groups. Next, we focused on constructing a human factors task analysis of both products. Finally, we conducted a comparative risk assessment of the tasks that were different between the two products., Results: Inexperienced users, such as nonmedical first responders and bystanders, are at the highest risk of incorrectly administering naloxone, particularly in high-stress emergency opioid overdose situations. The device Preparation and Medication Delivery tasks most differentiate the use of NARCAN ® Nasal Spray and a PFS-NA. The level of task complexity and number of steps within those tasks is substantially greater for a PFS-NA than for the NARCAN ® Nasal Spray., Conclusions: NARCAN ® Nasal Spray requires fewer steps and is easier to administer than a naloxone PFS-NA. Thus, using NARCAN ® Nasal Spray should increase the likelihood that nonmedical personnel correctly deliver naloxone in time-critical, high-stress opioid overdose rescue situations., Funding: ADAPT Pharma, Inc.