Background The human ELFN1 encodes a functional protein belonging to leucine-rich repeat (LRR) family neuronal adhesion proteins. However, there remains a lack of research on ELNF1 in tumors, especially in colon adenocarcinoma (COAD). The paper aimed to explore ELFN1 expression and its potential biological function in COAD through bioinformatics analysis. Results ELFN1 expression was significantly upregulated in COAD tissues from The Cancer Genome Atlas (TCGA) database (P<0.01). The high ELFN1 mRNA expression level in tumor samples was also verified in GSE39582 and GSE146009 cohorts from Gene Expression Omnibus (GEO) website (P<0.01). Besides, high ELFN1 expression was positively correlated with advanced tumor stage (I vs. IV, II vs. IV), perineural invasion,and vascular invasion (P<0.05). Moreover, high ELFN1 expression was correlated with worse overall survival (OS) (P<0.05), which was also verified in GSE17536 and GSE29621 datasets (P<0.05). Multivariate Cox regression analysis suggested ELFN1 was an independent prognostic predictor in COAD (P<0.01). Furthermore, the high infiltration levels of M0 Macrophages and Regulatory T cells(Tregs)were found in the high ELFN1 expression COAD tissues, while the infiltration levels of activated CD4 memory T cells, resting or activated Dendritic cells were low in that samples (P<0.05). The correlation analysis revealed that ELFN1 expression had a positive correlation with the infiltrating levels of Tregs and M0 Macrophages, but inversely correlated with that of activated Dendritic cells and both resting and activated CD4 memory T cells in COAD (P<0.05). Gene Set Enrichment Analysis (GSEA) exhibited that ELFN1 was enriched in many immunological and cancer-related signaling pathways, like Hedgehog, ECM receptor interaction, focal adhesion, Notch, and MAPK signaling pathways.Conclusions ELFN1 is overexpressed in COAD and which is correlated with worse clinical outcomes. Higher expression of ELFN1 could influence tumor immune cells infiltrating in COAD. ELFN1 could promote progression of COAD through several immunological and cancer-related signaling pathways. ELFN1 may be a new prognostic predictor and a latent therapeutic target for COAD.