The polymeric immunoglobulin receptor (PIGR), an exosome-associated glycoprotein, plays an important role in the occurrence and development of different tumors. This study aimed to investigate whether PIGR is essential for colorectal cancer (CRC). Comprehensive bioinformatics analysis and immunohistochemistry (IHC) revealed that expression of PIGR was significantly decreased in CRC patients. Upregulated PIGR displayed favorable prognostic values in CRC patients. Several algorithms, such as TISIDB and TIMER, were used to evaluate the roles of PIGR expression in the regulation of immune response in CRC. Moreover, GSEA enrichment analysis indicated the underlying role of PIGR in the regulation of fatty acid metabolism in CRC. Taken together, our findings might provide a new potential prognostic and immune-associated biomarker for CRC and supply a new destination for PIGR-related immunotherapy in clinical treatment.