Novel acid-labile, thermoresponsive methacrylamide-based (co)polymers with pendent ortho ester groups were prepared by free radical polymerization of N-(2-methoxy-1,3-dioxan-5-yl)methacrylamide (NMM) and N-(2-ethoxy-1,3-dioxan-5-yl)methacrylamide (NEM). These polymers are both thermoresponsive and acid-sensitive in aqueous solution, which was proved by transmittance measurements, fluorescence, and H-1 NMR spectroscopy. The LCSTs of the (co)polymers were shifted to higher temperature by increasing the content of the more hydrophilic NMM units. All of these polymers can be hydrolyzed under acidic condition and the hydrolysis rate increased with the decrease in the pH value.