Background: The programmed death 1 (PD-1) pathway is up-regulated in the immune microenvironment of many cancers. PD-1 blockage has been shown to be effective in treating some malignancies. In colorectal cancers, inhibition of PD-1 pathway appears to be selectively efficacious in microsatellite instable (MSI) tumors. In this study, we examined the immune microenvironment of small intestinal adenocarcinoma by immunohistochemistry. Methods: Twenty two small intestinal adenocarcinomas were identified from our Pathology Archives from 01/01/2002 to 05/01/2014. Immunohistochemical studies were employed to evaluate expression of CD3, CD4, CD8, CD20, CD56, PD-1 and programmed death ligand 1 (PD-L1). CD3+, CD4+, and CD8+ T cells were estimated under high power fields (HPF) and compared between PD-L1+ and PD-L1- tumors. Results: The 22 cases included 9 females and 13 males, with age ranging from 38 to 92 years. PD-1 was expressed in 18 of 22 (82%) cases, by tumor surrounding lymphocytes and lymphoid aggregates as well as tumor infiltrating lymphocytes if present. PD-L1 expression was observed in 10 of 22 (45%) cases, including 2 MSI, 2 microsatellite stable (MSS) and 6 tumors with unknown MSI status. PD-L1 was mainly expressed by histiocytes capping cancerous glands/nests at the infiltrating front. Expression of PD-L1 was also seen in tumor cells surrounding by the histiocytic caps. All the 10 cancers also expressed PD-1. The tumors expressing PD-L1 contained more CD3+ (440±22/HPF versus 238±31/HPF, p < 0.01), CD4+ (172±26/HPF versus 287±25/HPF, p < 0.01) and CD8+ T cells (58±17/HPF versus 153±33/HPF, p = 0.013) than those without expression of PD-L1. CD20+ cells were mainly seen in lymphoid aggregates. There were rare or none C56+ inflammatory cells. Conclusions: PD-1 and PD-L1 are expressed by inflammatory cells (mainly histiocytes) and tumors cells in most small intestinal adenocarcinoma. Blockage of the PD-1 pathway should be evaluated in the treatment of small intestinal adenocarcinomas.