We evaluated the association of cell adhesion molecule 4 (CADM4) expression with clinicopathologic parameters and overall survival (OS) in patients with small intestinal adenocarcinomas (SIAs) and determined its prognostic significance. CADM4 immunohistochemical staining was performed for 170 SIA samples. Loss of or low CADM4 expression was observed in 26 (15.3%) and 50 (29.4%) cases, respectively, and it was significantly associated with undifferentiated histology (p < 0.044), high-grade tumor (p < 0.001), high pT3 or pT4 stage (p < 0.038), pancreatic invasion (p < 0.018), and lymphatic invasion (p < 0.020). Patients with CADM4 expression loss had significantly poorer OS (p < 0.042). On multivariate analysis, SIA in the jejunum and ileum, (hazard ratio [HR], 2.465; 95% confidence interval [CI], 1.288-4.720; p = 0.006 and HR, 3.407; 95% CI, 1.515-7.662; p = 0.003, respectively), signet ring cell carcinoma (HR, 92.388; 95% CI, 14.813-576.230; p = 0.000), SIA with lymph node metastasis (HR, 3.223; 95% CI, 1.697-6.124; p = 0.000), retroperitoneal seeding (HR, 3.696; 95% CI, 1.303-10.479; p = 0.014), and CADM4 expression loss (HR, 2.348; 95% CI, 1.130-4.882; p = 0.022) were associated with poor OS. CADM4 expression loss is an important prognostic marker for SIA.