Flotation separation of chalcopyrite from talc is difficult because of the natural hydrophobicity of two minerals. In this work, the flotation separation of chalcopyrite from talc using N-carboxymethyl chitosan as a depressant for talc was studied. The micro-flotation results indicated that the flotation separation of chalcopyrite from talc cannot be realized effectively at pH 9 with low concentration of N-carboxymethyl chitosan, in the presence of calcium ions, talc was more efficiently depressed by N-carboxymethyl chitosan, while the chalcopyrite recovery was not influenced. Contact angle, zeta potential and adsorption results showed that Ca2+ and CaOH+ absorbed on the talc surface and increased the absorption amount of N-carboxymethyl chitosan on the mineral surface, and increased hydrophilicity of talc surface, resulting the selective depression for talc in chalcopyrite flotation.