Interleukin-16 (IL-16) is reported to play an important role in inflammation, carcinogenesis and tumoricidal processes, however, the contribution of IL-16 genotype to oral carcinogenesis is still largely unrevealed. Thus, the study aimed to investigate the contribution of IL-16 genotypes to Taiwan oral cancer risk. The genotypes of IL-16 rs4778889, rs11556218, and rs4072111 were revealed among 958 oral cancer cases and 958 control subjects by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). First, the distributions of genotypic (p=0.0004) and allelic (p=0.0001) frequencies of IL-16 rs11556218 were significantly different between the case and control groups. In detail, the frequencies of IL-16 rs11556218 TG and GG were 28.1 and 5.8%, respectively, among oral cancer patients, significantly higher compared to those among controls (25.0% and 2.7%, respectively). Second, no difference was observed regarding IL-16 rs4778889 or IL-16 rs4072111. Last, there was a synergistic effect of betel quid chewing behavior and risky IL-16 rs11556218 genotype on oral cancer risk. The study indicates that the IL-16 rs11556218 G allele synergistically interacts with betel quid chewing behavior, contributing to increased risk of oral cancer in Taiwanese.