In conclusion, our study showed that ESR1 IVS1-397C>T (rs2234693), ESR1 IVS1-351A>G (rs9340799), ESR2 -789 A>C (rs1271572) polymorphisms and their higher-order interactions may confer increased risk of gallbladder carcinoma, probably through gallstone mediated pathway. The gene discussed is ESR2; the disease is gallstones.