Background: Recent evidence suggested that IL1RN (interleukin-1 receptor antagonist) polymorphisms increased the susceptibility to cancers. The present study aimed to evaluate whether IL1RN was related to esophageal cancer susceptibility in a Northwest Han Chinese population. Methods: The case-control study was conducted on 384 esophageal cancer patients and 499 healthy controls. We successfully genotyped four SNPs distributed in IL1RN. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to observe the expression of IL1RN in esophageal cancer tissues and normal tissues. RegulomeDB and HaploReg v4.1 were used to calculate possible functional effects of the polymorphisms. We also used genetic models to detect any potential association between IL1RN variants and esophageal cancer risk. Results: In our study, rs3181052 was associated with a reduced risk of esophageal cancer in the codominant (odds ratio [OR] = 0.70, 95% confidence interval [CI] 0.52–0.93, p = 0.040), the dominant (OR = 0.75, 95% CI 0.57–0.99, p = 0.041), and the overdominant (OR = 0.71, 95% CI 0.54–0.93, p = 0.012) model. The rs452204 was associated with a 0.76-fold (OR = 0.76, 95% CI 0.58–0.99; p = 0.043) decreased esophageal cancer risk under the overdominant model without adjustment. We also found that rs3181052 had a negative effect on esophageal cancer under the overdominant model (OR = 0.72, 95% CI 0.53–0.97, p = 0.033) adjusted for age and gender. In stratified analyses by age >55 years, rs3181052 reduced the risk of esophageal cancer in the dominant and overdominant models. In addition, rs315919 had a remarkable influence on esophageal cancer risk in females, while the association was not significant between rs3181052 and esophageal cancer risk in males. Conclusions: Our study provided the first evidence that IL1RN rs3181052, rs452204, and rs315919 are correlated with a decreased risk of esophageal cancer in a Northwest Han Chinese population. These findings may be useful for the development of early prognostics for esophageal cancer. However, further larger studies on different ethnic populations are warranted to verify these findings.