Interleukin (IL)-1B reportedly promotes the stemness and invasiveness of colon cancer cells. Several studies have investigated the association between IL-1B gene polymorphisms and colorectal cancer (CRC) risk, but report conflicting findings. Here, this association was explored in a hospital-based case-control study involving 527 CRC cases and 639 controls from two Chinese Han populations. Genotyping was done by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The IL-1B expression in CRC patients and controls were obtained from the GEPIA database and the mRNA expressions of different genotypes were downloaded from the GTEx portal database. The relationship of two IL-1B gene loci with clinical parameters and overall survival were analyzed using the Chi-square test and Kaplan-Meier analysis with the log-rank test respectively. It was found that the IL-1B mRNA levels in CRC patients were significantly higher than in controls. Bioinformatic analysis suggested that rs1143634 and rs1143623 polymorphisms decreased the IL-1B mRNA expression. The two polymorphisms were associated with decreased risk for CRC. Stratified analyses revealed the IL-1B gene rs1143623 and rs1143634 polymorphisms decreased the risk of CRC among females, smokers and drinkers. Moreover, the CC and/or GC genotype of rs1143623 polymorphism were correlated with decreased risk among CRC patients with tumor size ≥5cm, TNM stage III+IV, and rectal cancer. For rs1143634 polymorphism, the CT genotype reduced the risk of colorectal adenocarcinoma. The CRC patients carrying CC genotype of rs1143623 polymorphism were associated with better overall survival. In conclusion, IL-1B gene rs1143623 and rs1143634 polymorphisms are associated with decreased risk for CRC patients and thereby play important roles in the etiology of CRC.