AimsGastric neuroendocrine carcinoma (NEC) is a rare and aggressive subtype with a poor prognosis. We aim to investigate expression profiles of HER2 and programmed death ligand 1 (PD‐L1) in gastric NEC to test the potential applicability of drugs targeting these molecules.Methods and resultsExpression levels of HER2 and PD‐L1 were evaluated in 25 gastric NECs, including 10 pure NECs and 15 mixed adenocarcinoma–NECs, and a combined positive score (CPS) was used to evaluate PD‐L1 expression. The correlations of expression levels with both clinicopathological features and the expression of p53, retinoblastoma protein (Rb) and mismatch repair proteins were also analysed. Eighteen of the 25 (72%) cases showed a PD‐L1 CPS of ≥ 1, which was previously shown to be associated with response to pembrolizumab. Positive nodal metastasis and low tumour‐infiltrating lymphocyte (TIL) levels at the invasive margin were significantly associated with a PD‐L1 CPS of < 1. The NEC component was HER2‐negative in all cases, whereas HER2 positivity was observed in the adenocarcinoma component of six of 15 (40%) mixed adenocarcinoma–NECs. Mismatch repair deficiency, a mutant pattern of p53 expression and loss of Rb expression were observed in four (16%), 17 (68%) and nine (36%) cases, respectively, although these alterations were not associated with the PD‐L1 CPS or other clinicopathological characteristics.ConclusionsHER2 is unlikely to be an effective target in gastric NEC owing to the lack of HER2 expression, whereas the PD‐1/PD‐L1 pathway is a potential therapeutic target for gastric NEC because of the relatively high prevalence of a PD‐L1 CPS of ≥ 1 in this subtype.