Objective <p>To estimate the association between publicly provided take-home naloxone kits and opioid-related deaths.</p> Methods <p>We analyzed 2732 opioid-related deaths and the distribution of 147,814 naloxone kits between January 2015 and June 2019 across five health zones in Alberta, Canada. We used a Poisson pseudo-maximum likelihood regression model with fixed effects to estimate the association between the number of kits in circulation and the number of monthly opioid-related deaths, controlling for population demographics, socio-economic indicators, other harm reduction strategies, police seizures of fentanyl and carfentanil, and an estimate of awareness.</p> Results <p>Every 10,000 kits in circulation was associated with a 23.9% (95% confidence interval&#xa0;(CI), 12.6–33.7) reduction in opioid-related deaths. Marginal analysis suggests that if no kits had been distributed, Alberta would have had 3548 deaths (95% CI, 2264–4831), 816 more deaths than were recorded during this 4.5-year period. If during this time 200,000 kits were consistently in circulation, Alberta would have had an estimated 1587 deaths (95% CI, 705–2468), 1145 fewer deaths than recorded.</p> Conclusion <p>This analysis provides evidence that the availability of naloxone kits is associated with a reduction in opioid-related deaths and suggests that a publicly funded program that allows the distribution of naloxone kits to all who request them reduces mortality.</p>