GWAS have reported SNPs in immune-related genes to risk or prognosis. Interferons are immunerelated proteins produced and released by host cells in response to the presence of pathogens. IFN-mediated signaling has a diverse range of functions, including antiviral and antimicrobial response, antiproliferation, immunomodulation and apoptosis. There are two main classes of IFNs, type I and type II. The two type I IFNs, IFNA and IFNB, have been reported to have an effect on tumor suppression and antiviral immune defense through induction of p53 responses. IFNG, the only type II IFN, has been suggested to play a vital role in the disruption of the intestinal epithelial barrier function. It has also been identified as an important modulator of immune-related genes, such as toll-like receptor 3, the gene which showed association with CRC survival in our previous study. Interferon regulatory factors regulate IFNs and some IFN-inducible oncogenes by serving as transcription mediators of pathogens and IFN-induced signaling pathways. Interferon receptors are essential for IFNs to exert their biological effects. All type I IFNs bind to a receptor composed of two subunits, IFNAR1 and IFNAR2, while the type II interferon IFNG binds to another dimeric receptor composed of IFNGR1 and IFNGR2. So far, few studies have investigated the association between genetic variants in the IFN signaling pathway and CRC. A previous study examined genetic variation in IFNG, IFNGR1, IFNGR2 and IRF1-9 with the risk and survival of colon and rectal cancer. In that study, tagSNP approach was applied; several SNPs in IRFs, IFNG and its receptors were found to be associated with CRC risk or survival. IFN-signaling system may play a critical role in carcinogenesis of CRC by ICG-001 regulating immune responses during inflammation and it may additionally affect survival of CRC patients. In this genetic association study, we investigated the associations between 34 SNPs capturing 74 potentially functional SNPs in the IFN-signaling system genes and CRC risk and clinical outcome. Two SNPs located in the IFNAR1 and IFNGR1 genes exhibited an association with CRC risk. In the multivariable survival analysis, the SNP rs6475526, located about 2.2 kb of IFNA14 and capturing two promoter SNPs in IFNA7, was associated with overall survival and also with event-free survival of non-metastatic CRC patients. These SNPs together with other common variants identified by the GWASs and the candidate gene studies may affect CRC risk and clinical outcome. IFNAR1 has recently been proposed as a novel candidate CRC tumor suppressor gene. IFNAR1 has also been reported to play an important role in the development of early-onset CRC, suggesting a role in genetic predisposition. Polymorphisms in IFNAR1 have also been reported to be associated with susceptibility of multiple sclerosis, hepatocellular carcinoma and outcome of hepatitis B virus infection.