Background: Hepatoid adenocarcinoma (HAD) and adenocarcinoma with enteroblastic differentiation (ACED) are rare types of gastric cancer that produce alpha-fetoprotein (AFP) and morphologically resemble liver or fetal gut cells. The molecular characteristics of these tumors are poorly understood. We aimed to investigate the molecular profile of HAD and ACED in the comparison with common type of gastric cancer. Methods: We analyzed tissue and blood samples from 496 patients who underwent gastrectomy for gastric cancer and participated in the Project HOPE (High-tech Omics-based Patient Evaluation) in our hospital, from 2014 to 2019. We excluded patients with other special types of gastric cancer, remnant gastric cancer and preoperative chemotherapy. We analyzed gene mutation, copy number, and gene expression between 10 HAD/ACED and 486 common types of gastric cancers. Results: The mutated genes with high frequency (> 20%) in HAD/ACED were TP53 (100%) CSMD3 (30%), LRP1B, FAT3, TG, APOB, CREBBP, PASK, DROSHA and STK40 (20%). The tumor mutation burden (TMB) of all the cases were less than 10. TMB of HAD/ACED was equivalent to that of common type of gastric cancer with microsatellite stable type. The copy number of 20q13.2 encoding SALL4 was significantly gained in HAD/ACED (p = 0.03). Furthermore, 17 genes were highly expressed in these tumors, and many of these genes were associated with hepatocytes and fetal organs, including LIN28B, IGF2BP1, and HMGA2, which are related to TP53 mutation. Conclusions: Our molecular profiling revealed similarities between HAD/ACED and hepatocytes/fetal organs and high expression of LIN28B, IGF2BP1 and HMGA2, which are associated with TP53 inactivation. These results suggest that these genes may define morphological features of HAD/ACED.