AbstractEsophageal neuroendocrine neoplasms (NEN) are extremely rare and little is known about their risk factors. To identify the potential risk factors, we evaluated whether the history of substance use, including alcohol, tobacco and areca nut consumption was associated with esophageal NEN. Forty‐one esophageal NEN patients diagnosed between 2002 and 2019 from 17 hospital in Taiwan were enrolled as the cases. Controls were participants who received complete esophagogastroduodenoscopy in an endoscopic cohort and 123 eligible controls were matched to 41 cases (3:1) on age and gender. Alcohol drinking and cigarette smoking significantly increased the risk of esophageal NEN, with about a fourfold risk increase in alcohol drinkers as well as cigarette smokers. Moreover, use of cigarette smoking and alcohol consumption in combination demonstrated the highest risk of esophageal NEN with the risk increasing up to 20 times compared with non‐users. Alcohol consumption and cigarette smoking significantly increase risk of esophageal NEN and both alcohol and cigarette users had the highest risk.