Objective: To investigate the association of the genetic variation in the promoter region of microRNA 22 (miR-22) and the susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in Chinese population. Methods: Using a case-control approach, the venous blood samples from 1 020 HBV-positive HCC patients (case group) and 1 046 healthy subjects (control group) were collected. The genotypes of the polymorphic sites, rs6502892 (C→T) and rs721576 (A→G), in the promoter region miR-22 gene were determined by TaqMan allelic discrimination assay. According to the general data of the enrolled subjects, the relationships between different genotypes and risk of HBV-related liver cancer were analyzed by Logistic regression. Results: The rs6502892 genotype distributions had statistical difference between case group and control group (P=0.018), while the rs721576 genotype distributions showed no statistical difference (P>0.05). Compared with the rs6502892 wild-type (CC), the variant rs6502892 genotypes (CT/TT) showed a significantly increased risk of HBV-related liver cancer (adjusted OR=1.23, 95% CI=1.02–1.47, P=0.029). Further stratified analysis showed that the risk effect of variant rs6502892 genotypes (CT/TT) was more evident in those less than 52 years of age, and in females, smokers and alcoholics (all P<0.05), however, the variant rs721576 genotypes (AG/GG) showed decreased risk of HBV-related liver cancer in males and non-smokers (both P<0.05). Conclusion: In Chinese population, the variant rs6502892 genotypes (CT/TT) of miR-122 gene are associated with an increased risk of HBV-related liver cancer, whereas, the risk of HBV-related liver cancer is decreased in men and non-smokers with variant rs721576 genotypes. However, this conclusion still needs further confirmation with genetic association and functional studies.