Chronic infection of viral hepatitis is the main cause of liver cancer. There were many studies assessing the associations of methylenetetrahydrofolate reductase (MTHFR) Ala222Val polymorphism with risks of hepatitis and hepatitis-related liver cancer, but no consistent results were reported. To investigate the associations of MTHFR Ala222Val polymorphism with risks of hepatitis and hepatitis-related liver cancer, we performed a meta-analysis of published case-control studies. Eligible studies were searched from PubMed and Chinese National Knowledge Infrastructure (CNKI) databases. The odds ratio (OR) and corresponding 95 % confidence interval (95 %CI) were used to assess the associations. Twenty-one individual studies with a total of 8,187 subjects were included. Overall, MTHFR Ala222Val polymorphism was not significantly associated with risks of liver cancer, hepatitis-related liver cancer, and non-hepatitis-related liver cancer. However, MTHFR Ala222Val polymorphism was significantly associated with risk of hepatitis infection (Val vs. Ala: OR = 1.15, 95 %CI 1.01-1.32, P = 0.03; ValVal/AlaVal vs. AlaAla: OR = 1.37, 95 %CI 1.11-1.68, P = 0.003). Therefore, MTHFR Ala222Val polymorphism is significantly associated with risk of hepatitis infection but not liver cancer. More studies are needed to further assess the association between MTHFR Ala222Val polymorphism and hepatitis-related liver cancer.