Sun CLF, Karlsson L, Morrison LJ, et al. - In view of the possibility of achieving improved automated external defibrillator (AED) accessibility and out‐of‐hospital cardiac arrest (OHCA) outcomes with mathematical optimization of AED placement vs American Heart Association (AHA) and European Resuscitation Council (ERC) placement guidelines, an in silico trial (simulated prospective cohort study) was performed to compare mathematically optimized placements vs placements derived from current AHA and ERC guidelines, which recommend placement in locations where OHCAs are generally witnessed. From 2008 to 2016, all public OHCAs of presumed cardiac cause were identified in Copenhagen, Denmark. For the control, researchers computationally simulated placing 24/7‐accessible AEDs at every unique, public, witnessed OHCA location at monthly intervals over the study period. Three hundred ninety three AEDs at historical, public, witnessed OHCA locations were involved in the control scenario, covering 15.8% of the 653 public OHCAs from 2008 to 2016. Per Observations, significant improvement in OHCA coverage as well as in estimated clinical outcomes can be attained with mathematical optimization compared with a guidelines‐based approach to AED placement.