<b><i>Objectives:</i></b> Small intestinal adenocarcinoma (SIAC) is an exceedingly rare human malignant tumor, and its association with the S100A14 gene is not known yet. We aimed to investigate the clinicopathological correlations between S100A14 expression and SIAC. <b><i>Methods:</i></b> Immunohistochemical analyses of S100A14, p21 and p53 were performed using tissue microarray analysis of 175 surgically resected SIACs. <b><i>Results:</i></b> Of 175 SIACs, loss of S100A14 expression was observed in 128 cases (73.1%). Loss of S100A14 expression was associated with lymph node metastasis (p<i> = </i>0.009) and advanced disease stage (p<i> = </i>0.013), and was more frequently observed in distal than duodenal tumors (p<i> = </i>0.043). The majority of SIACs lost p21 expression (93.7%), and significant loss of p21 expression was observed in cancers with high pT stages (pT₃ and pT₄; p = 0.011), lymph node metastasis (p = 0.029) and advanced cancer stage defined by the American Joint Committee on Cancer (p = 0.005). Overexpression of p53 was found in 23.4% of cases. Positive expression of p53 was associated with distally located SIACs (jejunum or ileum; p = 0.006). There was no association between the expression of S100A14 and p21 or p53. <b><i>Conclusion:</i></b> Loss of S100A14 in SIAC is common and is associated with higher metastatic potential and advanced clinical stage.