In colorectal carcinoma (CRC), the presence of an interferon (IFN)-γ immune signature has been associated with an improved clinical outcome. This response is characterized by high expression levels of IFN-γ and interferon-stimulated genes (ISGs), including guanylate-binding protein 1 (GBP-1). We previously reported that GBP-1 expression can be specifically lost in tumor but not stromal cells in CRC, indicating a resistance to IFN-γ. Here, we investigated the IFN-γ response in CRC cell lines and found that ISGs expression and IFN-γ-induced cell death were inhibited in 6 out of 11 CRC lines (non-responders). Analysis of the IFN-γ response pathway revealed no significant driver mutation of the pathway genes IFNGR1, IFNGR2, JAK1, JAK2 and STAT1. At the mRNA level, IFNGR1 expression was downregulated in 4 non-responder cell lines. Treatment with decitabine, a DNA methylation inhibitor, increased IFNGR1 mRNA expression, suggesting an epigenetic regulation of the receptor expression. In CRC, a low mRNA expression of IFNGR1 but not of IFNGR2, STAT1, JAK1 or JAK2 correlated with a reduced disease-free survival in two patients cohorts. At the protein level, IFNγRα (coded by IFNGR1) was undetectable in the 4 non-responder lines showing a reduced mRNA expression and mis-glycosylated in the two remaining resistant cell lines. In a cohort of 363 CRC patients, absence IFNγRα protein expression in tumor cells was significantly associated with a reduced cancer-related survival. In addition, mice with a conditional knockout of the IFN-γ receptor in intestinal epithelial cells developed more tumors than control mice in a carcinogen-induced colon tumorigenesis model, indicating that the absence of IFN-γ receptor expression in intestinal epithelial cells fosters tumor growth. Reconstitution of IFNγRα expression in non-responder cells by transfection failed to reinstate the sensitivity to IFN-γ. In all non-responder cell lines, IFNγRα, either intrinsically or ectopically expressed, was mis-glycosylated. Lectin staining showed an overall reduction of glycosylation in nonresponders compared to IFN-γ-sensitive cell lines, and the expression of N-glycosylation enzymes was deregulated in non-responder cells. Treatment with different N-glycosylation inhibitors abrogated the IFN-γ signalling in responder cells. In addition, both IFNγRα expression and the presence of complex N-glycans were reduced in tumor samples compared to matching normal tissues. Treatment of non-responder cells with MG132 resulted in increased IFNγRα protein expression, indicating that improperly glycosylated IFNγRα is degraded by the proteasome. Altogether, our data showed that the loss of IFN-γ response in CRC is regulated by the glycosylation status of IFNγRα and indicate that dysfunction of the glycosylation pathway, by destabilizing IFNγRα, is involved in immune escape mechanisms of CRC.