The present invention relates to a method for increasing the oxygen release efficiency of a hemoglobin-based blood substitute by using a phthalide compound, comprising the steps of: administering to a subject in need thereof the phthalide compound or co-administering to the subject in need thereof the phthalide compound along with the hemoglobin-based blood substitute, wherein the phthalide compound has an effect of increasing the oxygen release efficiency of the hemoglobin-based blood substitute, wherein the hemoglobin-based blood substitute can be fetal hemoglobin (HbF) or other Hb variants retaining two native α subunits. The phthalide compound is used to substitute for or cooperate with 2,3-BPG, to play a role of a 2,3-BPG substitute, to act on the hemoglobin-based blood substitute to effectively substitute the function of normal hemoglobin in releasing oxygen to tissue cells, in order to maintain the cellular oxygenation level within a normal range.
