The mannose 6-phosphate/insulin like growth factor II receptor (CD222, M6P/IGFIIR) is a multifunctional transmembrane type I receptor, mostly localized intracellularly, less on the cell surface of all types of mammalian cells. It is known both to transport lysosomal enzymes through their mannose 6-phosphate moieties and to internalize extracellular ligands like IGFII or plasminogen. CD222 is involved in regulation of cell proliferation, migration, T cell activation and apoptosis. CD222 might also be released from endothelial cells in a soluble form. In this study, we analysed the level of soluble CD222 (sCD222) in sera of cancer patients. We found the elevated levels of sCD222 in sera of cancer patients compared to healthy donors irrespective to the type of disease suggesting a general role for sCD222 in tumorigenesis. Indeed, we found that TGF-β, a cytokine associated with the process of tumour progression, increased the shedding of CD222. Our findings identify in sCD222 a potential biomarker of tumorigenesis.