Compared with the MDM4 rs4245739 AA genotype, a significantly decreased risk of ESCC was associated with AC and CC genotypes only among females (OR = 0.46, 95% CI = 0.26–0.80, P = 0.006), but not among males (OR = 0.74, 95% CI = 0.53–1.03, P = 0.074). Here, MDM4 is linked to esophageal squamous cell carcinoma.