Chitosan hydrochloride-alginate microparticles were prepared by homogeneous emulsification method. Choosing doxorubicin hydrochloride as model drug, three types of microparticles were fabricated using three kinds of metal cations (Ca²⁺, Zn²⁺, Cu²⁺) as cross-linkers respectively, the effects of different metal cations on the drug loading capacity and drug release efficiency of microparticles were investigated. The results manifest that chitosan hydrochloride- calcium alginate, chitosan hydrochloride- zinc alginate and chitosan hydrochloride- copper alginate microparticles loaded with doxorubicin hydrochloride are round in shape and uniform in size, the average microparticles size is 2.56 μm, 2.78 μm and 1.81 μm, and the entrapment efficiency is 97.22%, 98.01% and 41.29%, espectively. The drug release was simulated in PBS (pH= 6.8) at constant temperature and speed, and it is confirmed that the types of metal cations have significant effects on the entrapment efficiency and drug release property. These results indicate that all three groups of metal cations could be used as cross-linking agents for the preparation of the microparticles. Considering of toxicity, the microparticles that cross-linked by Ca²⁺, Zn²⁺ could be more suitable used as micro- drug carriers, which could provide a new strategy in designing doxorubicin hydrochloride- loaded drug vehicles.