Octadecyl quaternized carboxymethyl chitosan (OQCMC) was synthesized through carboxymethyl chitosan grafting with glycidyl octadecyl dimethylammonium chloride. By a solvent evaporation method, the drug delivery system was prepared based on poly(lactic-co-glycolic acid) (PLGA) block copolymers, hydroxyethyl cellulose and OQCMC, which was tried to load minocycline hydrochloride. The microspheres were characterized by transmission electron microscopy (TEM), quasielastic laser light scattering with a Malvern Zetasizer, H-1 NMR and FTIR. The results showed that the complex delivery system was good to load the minocycline hydrochloride and could provide long-term release behaviour through drug release experiment in vitro. The drug loading efficiency of minocycline hydrochloride could reach 9.4% by using the polymer surfactant OQCMC. It is good to decrease the particle size [(166.4 +/- 0.8) nm], increase the Zeta potential and keep the stabilization of the microspheres.