The significance of medical errors is widely appreciated. Given the frequency and significance of errors in medicine, it is important to learn how to reduce their frequency; however, the identification of factors that increase the likelihood of errors poses a considerable challenge. The National Emergency Department Safety Study (NEDSS) sought to characterize organizational- and clinician-associated factors related to the likelihood of errors occurring in emergency departments (EDs). NEDSS was a large multicenter study coordinated by the Emergency Medicine Network (EMNet; www.emnet-usa.org). It was designed to determine if reports by ED personnel about safety processes are significantly correlated with the actual occurrence of errors in EDs. If so, staff reports can be used to accurately identify processes for safety improvements. Staff perceptions were assessed with a survey, while errors were assessed through chart review of three conditions: acute myocardial infarction, acute asthma, and reductions of dislocations under procedural sedation. NEDSS also examined the characteristics of EDs associated with the occurrence of errors. NEDSS is the first comprehensive national study of the frequency and types of medical errors in EDs. This article describes the methods used to develop and implement the study.