Summary The adverse event (AE) profile of lay volunteer CPR and public access defibrillation (PAD) programs is unknown. We undertook to investigate the frequency, severity, and type of AE's occurring in widespread PAD implementation. Design A randomized-controlled clinical trial. Setting One thousand two hundred and sixty public and residential facilities in the US and Canada. Participants On-site, volunteer, lay personnel trained in CPR only compared to CPR plus automated external defibrillators (AEDs). Intervention Persons experiencing possible cardiac arrest receiving lay volunteer first response with CPR + AED compared with CPR alone. Main outcome measure An AE is defined as an event of significance that caused, or had the potential to cause, harm to a patient or volunteer, or a criminal act. AE data were collected prospectively. Results Twenty thousand three hundred and ninety six lay volunteers were trained in either CPR or CPR + AED. One thousand seven hundred and sixteen AEDs were placed in units randomized to the AED arm. There were 26,389 exposure months. Only 36 AE's were reported. There were two patient-related AEs: both patients experienced rib fractures. There were seven volunteer-related AE's: one had a muscle pull, four experienced significant emotional distress and two reported pressure by their employee to participate. There were 27 AED-related AEs: 17 episodes of theft involving 20 devices, three involved AEDs that were placed in locations inaccessible to the volunteer, four AEDs had mechanical problems not affecting patient safety, and three devices were improperly maintained by the facility. There were no inappropriate shocks and no failures to shock when indicated (95% upper bound for probability of inappropriate shock or failure to shock = 0.0012). Conclusions AED use following widespread training of lay-persons in CPR and AED is generally safe for the volunteer and the patient. Lay volunteers may report significant, usually transient, emotional stress following response to a potential cardiac arrest. Within the context of this prospective, randomized multi-center study, AEDs have an exceptionally high safety profile when used by trained lay responders.