Background <p>Opioid overdose remains a leading cause of mortality in the USA. Although distributing naloxone to laypersons for use during witnessed opioid overdoses has been shown to effectively reduce overdose deaths, clinician awareness of naloxone prescribing remains low. Academic detailing (AD) has been reported to be an effective strategy to increase naloxone distribution to individuals at risk of opioid-related overdose/death.</p> Objective <p>This study evaluated the cost effectiveness of an academic detailing program aimed at promoting naloxone prescribing for adults at risk of opioid-related overdose compared to no intervention (non-AD program). </p> Methods <p>A Markov model with an integrated decision tree was developed to estimate the costs and outcomes associated with the AD program over a lifetime horizon from the US payer perspective. Model robustness was tested using sensitivity and scenario analyses.</p> Results <p>The results indicated that the AD program incurred a total direct cost of US$6280 and achieved 16.52 quality-adjusted life years (QALYs). In comparison, the non-AD program incurred a total direct cost of US$5971 and achieved 15.92 QALYs. The incremental cost-effectiveness ratio for the AD program was US$514 per QALY gained with an incremental net monetary benefit of US$29,739. Sensitivity and scenario analyses confirmed the robustness of these findings, which suggest that AD is a cost-effective strategy for improving survival and quality of life in individuals at risk of opioid overdose.</p> Conclusions <p>For decision makers seeking to address the opioid crisis, implementing an academic detailing program represents a cost-effective option at a willingness-to-pay threshold of US$50,000 per QALY gained.</p>