Recently we identified β-galactoside α(2, 6)-sialyltransferase (ST6Gal I) as a candidate biomarker for ionizing radiation. The expression of ST6Gal I and the level of protein sialylation increased following radiation exposure in a dose-dependent manner. We also found that radiation induced ST6Gal I cleavage and the cleaved form of ST6Gal I was soluble and secreted. Sialylation of integrin β1, a glycosylated cell surface protein, was stimulated by irradiation and this increased its protein stability. Overexpression of ST6Gal I in SW480 colon cancer cells that initially showed a low enzyme activity of ST6Gal I increased the sialylation of integrin β1 and also increased the stability of the protein. Inhibition of sialylation by transfection with neuramidase or by treatment with short interfering (si) RNA targeting ST6Gal I (Si-ST6Gal I) reversed the effects of ST6Gal I expression. In addition, ST6Gal I overexpression increased clonogenic survival following radiation exposure and reduced radiation-induced cell death and caspase 3 activation. In conclusion, we suggest that exposure to ionizing radiation was found to increase sialylation of glycoproteins such as integrin β1 by inducing the expression of ST6 Gal I, and finally protein sialylation contributed to cellular radiation resistance.