Abstract: Acid-sensitive acetalized-dextrans had great potential in the field of biomedical applications. However, the influence of substituent group on the acid-sensitivity of acetalized-dextrans was unclear. Herein, a series of acid sensitive acetalized-dextrans were prepared by decorating the dextran backbone with different hydrophocic groups, such as n-butyl, isobutyl, cyclohexyl, or tert-butyl, through the reaction of vinyl ethers with dextran by using pyridinium 4-toluenesulfonate as a catalyst. The structures of these acetalized-dextrans were confirmed by nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR), and the hydrolysis products were determined by NMR. The acetalized-dextrans were prepared in a similar hydroxyl substitution degree and all the acetalized groups had a noncyclic structure. The substitution degrees of the n-butyl-decorated, isobutyl-decorated, cyclohexyl-decorated and tert-butyl-decorated dextrans were 49.0%, 49.0%, 49.9%, 50.0%, respectively. The acid-sensitivity of these acetalized-dextrans was studied using UV-Vis spectrometry by dispersing acetalized-dextrans into water with different pH values and measuring the transmittance at different time points. The acid-sensitivity of acetalized-dextrans was depended on the type of the β carbon on the acetalized group. The n-butyl-decorated dextran required a relatively lower pH to hydrolyze than others, while the tert-butyl-decorated dextran possessed the highest acid-sensitivity among the obtained acetalized-dextrans. This work offered a simple way to adjust the acid sensitivity of acetalized-dextrans by adjusting the type of β carbon on the acetalized group.