Let-7 and Lin28 establish a double-negative feedback loop to affect several biological processes, such as differentiation of stem cell, invasion and metastasis, and tumorigenesis. In this study, we systematically investigated the associations between 6 potentially functional SNPs of let7 and Lin28 genes and the risk of oral cavity cancer with a case-control study including 384 oral cavity cancer cases and 731 controls. We found that the variant allele (T) of rs221636 of Lin28B was significantly associated with a reduced risk of oral cavity cancer [odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.58-0.92, P = 7.55 × 10(-3) in additive model]. Bioinformatics prediction indicated that rs221636 was located at the binding site of hsa-miR-548p in the 3' UTR of Lin28B. Luciferase activity assay also showed a lower expression level for rs221636 T allele compared with A allele. These findings indicated that rs221236 located at Lin28B may contribute to the risk of oral cavity cancer through the interruption of miRNA binding.