Background: Obesity is a well-known risk factor for the development of esophageal cancer (EC). However, the impact of underweight on esophageal squamous cell carcinoma (ESCC) has not been fully recognized to date. Therefore, we herein sought to determine the risk of EC in subjects with underweight. Methods: We analyzed the clinical data from a total of 264,084 individuals with the age of 40 years or older, who received healthcare checkups arranged by the national insurance program, between 2003 and 2008. Newly diagnosed EC was identified using the claims data during a median follow-up duration of 7.9 years. Results: The mean body mass index (BMI) of patients was 23.80 ± 3.05kg/m2, and 6,784 individuals (2.6%) were classified as being underweight (BMI < 18.5 kg/m2). During the study period, 278 individuals (0.1%) developed EC. It was determined that underweight and obesity—compared with normal weight—were significantly associated with 73% increased risk and 30% decreased risk of EC, respectively. Excess risk of EC in the underweight group was independent of age, gender, smoking, and alcohol consumption. Heavy alcohol use had a synergistically increasing effect for developing EC among those in the underweight group. Conclusions: The mean body mass index (BMI) of patients was 23.80 ± 3.05kg/m2, and 6,784 individuals (2.6%) were classified as being underweight (BMI < 18.5 kg/m2). During the study period, 278 individuals (0.1%) developed EC. It was determined that underweight and obesity—compared with normal weight—were significantly associated with 73% increased risk and 30% decreased risk of EC, respectively. Excess risk of EC in the underweight group was independent of age, gender, smoking, and alcohol consumption. Heavy alcohol use had a synergistically increasing effect for developing EC among those in the underweight group.