Objective To analyze the relationship between protein phosphatase 2A catalytic subunit alpha (PPP2CA) expression and prognosis and immune infiltration in colorectal cancer (CRC) patients, and further explore the mechanism about the development and progression of CRC. Methods The differences in PPP2CA expression levels between CRC tissues and normal tissues were analyzed using the gene chip database Oncomine and The Tumor Immune Estimation Resource (TIMER) database. The impact of PPP2CA expression levels on the prognosis of CRC patients was analyzed using The University of Alabama at Birmingham Cancer data analysis portal (UALCAN) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. To further understand the role of PPP2CA in CRC, the co-expression network of PPP2CA was constructed using LinkedOmics platform, followed by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Besides, the correlation between PPP2CA and immune infiltration was analyzed using TIMER and GEPIA databases. The gene mutation of PPP2CA in colon adenocarcinoma (COAD) were analyzed using c-BioPortal platform. Results PPP2CA was down-regulated in CRC tissues compared with normal tissues, and higher PPP2CA expression indicated better Overall Survival (OS) and Progression-Free Survival (PFS). In COAD, the expression level of PPP2CA was positively correlated with immune infiltrating cells including CD8+ T cells, neutrophils and dendritic cells. However, certain immune cell markers including CD19 and CD38 in B cells, NOS2 in M1 macrophages, Arginase 1 (ARG1) and Mannose Receptor C-Type 1 (MRC1) in M2 macrophages, Human Leukocyte Antigen G (HLA-G) and CD80 in Tumor Associated Macrophage (TAM) and CD14 and Fc Gamma Receptor 3A (FCGR3A) in monocytes, showed a different pattern of PPP2CA-associated immune infiltration. In other words, PPP2CA expression level was significantly associated with B cells, macrophages, monocytes, TAM, Th1 cells, Th2 cells, regulatory T cells, exhausted T cells and neutrophils in both COAD and rectum adenocarcinoma (READ). Conclusion PPP2CA is down-regulated in CRC tissues and closely correlated with immune infiltration.