OBJECTIVES: Evzio is a naloxone autoinjector indicated for lay overdose reversal in emergency treatment of known or suspected opioid overdose. The cost effectiveness of prescribing Evzio for "lay overdose reversal" was compared to "no lay reversal" using a health system perspective over one year. METHODS: A decision analysis model was built using outcomes data obtained from randomized clinical trials and publicly available cost data. Adults at risk of heroin overdose in the US were included in the model. The primary outcome was Quality Adjusted Life Year (QALY). All data were subject to sensitivity analyses. RESULTS: In the base case analysis, Evzio was found to cost health systems an extra $24,126 for every additional QALY saved due to overdose. Sensitivity analyses of variables found that the model was sensitive to the probability of emergency medical services being called if no Evzio was given, the probability of an overdose being witnessed, and the probability of survival if no medical treatment was given. CONCLUSIONS: The cost per QALY saved in prescribing the naloxone autoinjector, Evzio, for patients at risk of opiate overdose is within acceptable cost effectiveness values for new therapies. When administered by friends, family members, and other witnesses of an opioid overdose, Evzio can be cost-effective.