We reported a rare case of primary hepatoid adenocarcinoma of gallbladder with Mab-21 domain containing 2 (MB21D2), polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12), and AT-rich interaction domain 2 (ARID2) mutations, which was confirmed after surgical resection pathologically.<h4>Case summary</h4>A 69-year-old female with distention of hypogastrium and constipation received enema treatment, but ineffectively. This evidence concerns the gene MB21D2 and hepatoid adenocarcinoma.