Background: Cholera has been an endemic disease in the Islamic Republic of Iran. According to surveillance system records and historical documents, cholera epidemics have led to thousands of mortalities throughout the country in past centuries. Aims: The aim of this study was an overview of cholera disease during the last five decades (1965-2014) and the epidemiological features of the last large-scale outbreaks in the Islamic Republic of Iran. Methods: In this descriptive study, cholera incidence data provided by the National Surveillance Database were extracted and significant fluctuating trends were tested using Cochran-Armitage test by Winpepi software, during 1965-2014. To realize the most associated factors of cholera incidence in the outbreaks, adjusted Odds Ratios (AORs) were computed by means of ordinal logistic regression using STATA, version 11. Results: Analysis of data has revealed a tremendous decrease of incidence trends from 19.7/100 000 to 0.01/100 000, with nine cholera epidemics that occurred with 5-6 year intervals during 1965-2014. Younger age groups (15-44 years) and inhabitants in urban areas have been more vulnerable to cholera in recent epidemics. However, the virulence of pathogens as well as case fatality rates have not changed during the last three epidemics. Conclusion: Burden of cholera disease in terms of case load has been dramatically reduced 1 / 10 WHO EMRO | The epidemiology of cholera in the Islamic Republic of Iran, 1965-2014 during 1965-2014. Furthermore, the epidemiological feature of cholera with regard to transmission route, place of inhabitant, age, immigration, mortality and antimicrobial resistance has changed considerably in recent epidemics. While the number of epidemic regions has diminished, some areas are still susceptible to cholera outbreaks.