We report here that: i) elevated IgG4-expressing cells occur especially in close vicinity to macrophages in CRC tissue; ii) higher levels of IgG4/-IgE ratios were found in metastatic compared to primary CRC disease, iii) in macrophages derived from healthy volunteers and different CRC patient groups, IgG4 stimulation could induce an immunoregulatory M2b-like macrophage phenotype, and iv) tumor antigen-specific IgG4 showed impaired antibody-mediated phagocytosis of tumor cells compared with IgG1. Here, IGHE is linked to colorectal carcinoma.