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Discharge against medical advice (AMA) depends on both patient population and hospital-related factors. No previous study has examined AMA discharges in Iran. The aim of this study was to determine the prevalence of AMA discharges and the associated factors in Iranian emergency department-admitted patients. In this prospective cross-sectional study, we studied 915 consecutive patients admitted to the emergency department of a major referral center in Iran. Patients were divided into two groups: those who left hospital AMA and those discharged with medical approval. Patients' characteristics in AMA and non-AMA groups along with reasons associated with AMA discharges were examined. Of 880 patients included, 178 (20.2%) were discharged AMA. Male sex, younger age, and a history of drug or alcohol abuse were not associated with AMA discharges. Lack of health insurance was found more frequently in patients discharged AMA (46.1 vs. 34.8%). Most AMA patients (63.0%) have been staying in hospital for less than 12 h. The most common reason stated by the patients for AMA discharge was dissatisfaction with care or diagnostic and therapeutic procedures (38.2%). This study identifies marked differences in prevalence and potential predictors of AMA discharges in Iran compared with what has been described in the literature. The high prevalence of AMA discharges after emergency admission in a developing country such as Iran calls for effective approaches to reduce the prevalence as well as further investigation into the responsible factors.