Objectives <p>Gastric SMARCA4-deficient undifferentiated tumors are rare and have a poor prognosis. We analyzed two cases of gastric SMARCA4-deficient undifferentiated tumors with clinicopathologic characteristics, treatment and flow-up.</p> Methods <p>Immunohistochemistry was used to evaluate the expression of BRG1 (SAMRCA4), SMARCB1 (INI-1), CKpan, Ki-67, CD3, CD20, CD163, PD-1, and PD-L1 in gastric SMARCA4-deficient undifferentiated tumors. Additionally, the clinical characteristics, imaging features, diagnosis, and treatment were analyzed.</p> Results <p>Two elderly male patients (69 and 61 years old) with a large ulcerated mass located in the gastric fundus and cardia. Histologically, the tumor is of low adhesion, diffusely infiltrating lamellar growth, without any percentage of epithelial differentiation zones, and with little stromal component. Tumor cells round, oval, a small amount of irregular shape, easy to see mitotic figures. Some of them had obvious nucleoli, and a few had multiple nucleoli. The cytoplasm varies, and some cells are more abundant. Significant vascular and neural invasion. BRG1(SMARCA4) was absent, INI-1 was present, and Ki-67 proliferation index was highly expressed (≥ 80%). The remaining sarcoma-specific markers were negative. In case 1, the epithelial markers were negative and the PD-L1 combined positive score was 5. In case 2, CKpan was weakly expressed in only a dozen cells, and the PDL1 CPS was 10. The two patients received chemotherapy and anti-PD1 immunotherapy after radical gastrectomy for gastric cancer. The postoperative follow-up time of the two patients was 16 (case 1) and 3 months (case 2), respectively. The general condition was good, no recurrence or metastasis was observed, and the plasma tumor markers were in the normal range.</p> Conclusions <p>Large SMARCA4-deficient tumors are more likely to have massive necrosis on the surface, leading to negative biopsy results. This tumor has a diffuse lamellar growth and needs to be differentiated from a variety of tumors with similar morphology, such as lymphoma, malignant melanoma, neuroendocrine carcinoma and undifferentiated sarcoma. The tumor cells were negative or only slightly positive for CKpan increases the difficulty of pathological diagnosis of this disease. However, loss of BRG1 (SMARCA4) expression can confirm the diagnosis. Chemotherapy combined with anti-PD1 treatment may have potential benefits in the management of gastric SMARCA4-deficient undifferentiated tumors. However, given the rarity of these tumors and the limited number of cases in our study, further research with larger cohorts is needed to validate these preliminary results.</p>