PurposeThis study aimed to elucidate the clinicopathological characteristics of α-fetoprotein (AFP)-producing gastric carcinoma (AFP-GC) with human epidermal growth factor receptor (HER)2 overexpression to extend the treatment strategy for AFP-GC.MethodsWe analyzed 41 patients with AFP-GC who underwent surgical resection or chemotherapy from 1989 to 2019, and who had over 20ng/mL of serum AFP or positive immunohistochemical AFP expression. HER2 expression status was investigated by immunohistochemistry (IHC) for all patients and by fluorescence in situ hybridization (FISH) for cases with an IHC score of 2+. AFP-GC with an IHC score of 3 + or 2 + and FISH positivity was defined as HER2 overexpressed AFP-GC. The correlation between HER2 status and clinicopathological characteristics and prognosis in AFP-GC was analyzed.ResultsHER2 overexpression was detected in 17.1% of AFP-GC patients. The prognosis of the patients with HER2 overexpressed AFP-GC was not significantly different compared to HER2 non-overexpressed AFP-GC. HER2 overexpressed AFP-GC consisted of heterogeneous histology with a higher proportion of mixed-type tumors (p = 0.002). The clinical outcome of AFP-GC with mixed-type of histology tended to be better than other intestinal or diffuse types (p = 0.05).ConclusionHER2 overexpressed AFP-GC consisted of a mixed type of histology, which showed a better prognosis. The results presented that HER2 status in AFP-GC is one of the molecular candidates to improve the prognosis.