Adsorption of CMC on galena (PbS) was investigated through electrokinetic, adsorption and ATR-FTIR spectroscopic studies. In addition, CMC adsorption on chalcopyrite (CuFeS2) was carried out to compare it to that on PbS. The effect of CMC on the floatability of PbS and CuFeS2 was assessed by microflotation using PbS and CuFeS2 crystals and ethyl xanthate as collector. Furthermore, the effect of oxidation of the minerals on the floatability and CMC adsorption was studied. CMC adsorption on PbS took place within a pH range of significant concentration of the hydroxo-complex species PbOH+ wherein the COOH group of the CMC is as COO-. It is proposed that CMC adsorbs through intramolecular electrostatic and acid/base interactions between the COO and PbOH+ at the PbS/aqueous solution interface. Adsorption of ethyl xanthate on PbS is more stable than that of CMC. Oxidation creates SO4 species on the PbS surface promoting co-adsorption of CMC, through which the PbS surface becomes hydrophilic on top of the hydrophobicity due to adsorbed ethyl xanthate. Upon oxidation, the high PbS floatability was largely hindered by CMC while that of CuFeS2 was not affected. Flotation strategies are presented for the application of the non-toxic polysaccharide CMC as a depressant of PbS in the separation of Pb-Cu bulk concentrates while floating CuFeS2.