Abstract: Objective To explore the association of allograft inflammatory factor-1 (AIF-1) gene polymorphisms, body mass index (BMI) and their interactions with susceptibility to oral cancer. Methods A case-control study including 300 patients with pathologically confirmed oral cancer from September 2010 to December 2016 and 445 cancer-free controls was performed. The genotypes were determined by TaqMan genotyping assay. Unconditional Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) to assess the association of AIF-1 gene polymorphisms, BMI and their interactions with susceptibility to oral cancer. Results In the co-dominant genetic model(OR=0.522, 95% CI:0.319-0.855) and the recessive genetic model(OR=0.573, 95% CI:0.368-0.893), subjects carrying GG genotype of rs2857595 had significantly reduced risk of oral cancer, respectively. Moreover, GG genotype was a clear protective factor in male, individuals with BMI ≥ 24.0 kg/m², and smoking and non-drinking subgroups. By contrast, BMI<18.5 kg/m² was a risk factor of oral cancer, and BMI ≥ 24.0 kg/m² reduced the risk of oral cancer. In addition, statistical analysis suggested an interaction between AIF-1 rs2857595 polymorphism and BMI. Conclusions This study suggests that AIF-1 rs2857595 polymorphism and BMI ≥ 24.0 kg/m² may be protective factors for oral cancer. And there may be a multiplicative interaction between AIF-1 and BMI.