Although periodate-oxidized dextran is widely used in biomedical applications, the degradation mechanism of oxidized dextran has not yet been elucidated. Herein, we propose a novel main chain scission mechanism of oxidized dextran triggered by reaction with amine. NMR analysis revealed four hemiacetal substructures during oxidation by periodate. Kinetic analysis showed that the degradation time constant of the C3-removed substructure and increasing time constant of the reducing end protons are consistent with the decrease in molecular weight determined by gel permeation chromatography. A methylene group is generated at the same time constant of degradation, indicating that oxidized dextran degradation proceeds via a Maillard reaction. Oxidized dextran does not degrade in saline solution without reactive amine species. Thus, we conclude that oxidized dextran is degraded in the main chain via Schiff base formation through a Maillard reaction, depending on the oxidation ratio and amino acid concentration. These findings help to elucidate the reaction mechanism of polysaccharide degradation and develop novel biodegradable polysaccharide materials for biomedical applications. (C) 2016 Wiley Periodicals, Inc.