The hydrolysis of colominic acid under microwave irradiation was studied and compared with traditional heating methods. The microwave irradiation has several advantages over the heating method in the hydrolysis of colominic acid: (a) products with higher degrees of polymerization are obtained, (b) less lactone byproducts are observed, and (c) the hydrolytic rate is much faster. These advantages are probably due to the microwave effect. Oligosialic acids as the products of the acid hydrolysis of polysialic acid with conventional heating methods were fully lactonized, especially under the conditions of higher temperature and stronger acid.