The S100A2 gene has been reported to be a putative tumor‑suppressor gene. Nevertheless, overexpression of S100A2 has been found in certain types of cancer. This study investigated S100A2 expression in tissue specimens of gastritis, intestinal metaplasia, adenomatous dysplasia and gastric cancer to determine its association with clinical features. A serial of tissue samples (gastritis, intestinal metaplasia, adenomatous dysplasia and gastric cancer samples) were used for quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical analyses of S100A2 expression. The data revealed that there was a gradual loss of S100A2 expression from gastritis, intestinal metaplasia and dysplasia to cancer tissue specimens (p<0.001). In gastric cancer samples, loss of S100A2 expression was associated with increased tumor size, depth of invasion, lymph node metastasis and a poor prognosis (p<0.001). However, the intestinal type of gastric cancer expressed more S100A2 protein than the diffuse type (p<0.001). In conclusion, data from the present study demonstrated that loss of S100A2 expression contributes to gastric cancer development and progression; therefore, the determination of S100A2 expression levels may help to predict the carcinogenesis and aggressiveness of gastric cancer as well as patient survival.