A carboxymethyl poly(L-histidine) has been synthesized as a new pH-sensitive polypeptide at endosomal/lysosomal pH. Because of its poor water solubility at physiological pH, an application of poly(L-histidine) with a pKa around 6.0 has been limited in spite of the native possession of the pH-dependent property change at endosomal pH. Although the unmodified poly(L-histidine) suddenly precipitates out of the aqueous medium above pH 6.0 as the result of the deprotonation of the imidazole groups, the water solubility of the resulting carboxymethyl poly(L-histidine) has been improved at physiological pH. A solution turbidity measurement proved that no significant effect on a rapid aggregate formation or phase separation of serum proteins is induced by carboxymethyl poly(L-histidine). Hemolysis assay showed that the carboxymethyl poly(L-histidine) enhances membrane disruptive ability at endosomal/lysosomal pH. The cellular uptake of luciferase in the presence of the carboxymethyl poly(L-histidine) increases intracellular luciferase activity, which suggests that the carboxymethyl poly(L-histidine) makes the luciferase escape from lysosomal degradation. The carboxymethyl poly(L-histidine) would be the fundamental compound for designing various drug carriers with the pH sensitivity at endosomal/lysosomal pH. Copyright © 2007 John Wiley & Sons, Ltd.