Abstract: Objective: To discuss the association between single nucleotide polymorphisms in let-7 and genetic susceptibility to head and neck cancer (HNC) in Han Chinese. Methods: In this case-control study, 503 newly and histologically confirmed HNC patients were consecutively recruited as cases and 900 cancer-free controls were randomly selected as controls. Designed questionnaires were used to acquire patients’ information on demographic data and age, sex, smoking, and alcohol consumption. Approximate 5 ml of venous blood sample was collected from each subject for DNA extraction and genotyping. We used TaqMan allelic discrimination assay to genotype two polymorphisms of rs10877887 and rs13293512 in let-7. The associations of SNPs with HNC risks were estimated by computing the crude and adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) using logistic regression analyses. Results: The frequencies of genotype TT, CT and CC of rs10877887 were 45.7% (227/503), 42.9% (213/503) and 11.4% (57/503) in case group; while separately 40.8% (361/900), 47.7% (422/900) and 11.5% (101/900) in control group. The frequencies of genotype TT, CT and CC of rs13293512 were 31.9% (157/503), 52.3% (257/503) and 15.8% (78/503); while separately 30.2% (270/900), 49.2% (439/900) and 20.6% (194/900) in control group. Logistic regression analyses showed that there was no statistic significe in the relationship between rs10877887 and susceptibility to HNC (CC+CT/TT：adjusted OR=0.82, 95% CI: 0.90-1.23, P=0.087), while rs13293512 CC genotype significantly decreased susceptibility to HNC (CC/TT+CT：adjusted OR=0.73, 95% CI：0.55-0.98, P=0.039). Conclusions: The polymorphism of rs13293512 in let-7 may be a biomarker of susceptibility to HNC in Han Chinese.