Objective:To investigate the expression of human epidermal growth factor receptor 2(HER2)and P53 and their relationship with microsatellite instability(MSI)in gastric cancer tissues.Methods:A total of 103 patients diagnosed with gastric cancer between January 2018 and October 2020 at Yueyang Hospital were enrolled in this study.HER2, P53 and mismatch repair proteins in gastric cancer tissues were detected with immunohistochemical(IHC)methods, and MSI screening was conducted at 7 sites with a new Idylla MSI(multiple fluorescent PCR)method.Results:Of 103 gastric cancer patients in this study, 77(74.8%)showed microsatellite stability(MSS)and 26(25.2%)showed MIS via IHC, and PCR also detected 77 MSS cases and 26 MSI cases.In MSI, there was more low HER2 expression than high HER2 expression, and the rate of low HER2 expression in MSI was higher than the rate of high HER2 expression in MSI( P<0.05).Also in MSI, there was more low P53 expression than high P53 expression, and the rate of low P53 expression in MSI was higher than the rate of high expression in MSI( P<0.05). Conclusions:MSS may exist in the process of gastric carcinogenesis and in gastric cancer it may be accompanied by low expression of HER2 and p53 in cancer tissues.There may be a mutually exclusive relationship between MSI and expressions of HER2 and p53, suggesting that carcinogenic mechanisms involving MSI may be very different from those involving HER2 and p53.MSI detection is very valuable in guiding treatment drug selection and prognosis assessment.