This paper presents and discusses measurements performed to study the interaction mechanism of calcium and sulfate with galena and their effect on xanthate adsorption. The results of collector adsorption show that regardless of the solution pH (5.5, 7.5 and 9.5), the presence of calcium and sulfate during the mineral preconditioning, decreases the adsorption of isopropyl xanthate onto galena. Microflotation measurements carried out at pH 9.5 show that at low concentrations of calcium and sulfate (below about 0.005 mol/L), the recovery of galena is not affected. However, as the concentration of both ions increases, flotation recovery substantially decreases. Contact angle measurements corroborate this behavior: a relatively large contact angle in the absence of calcium and sulfate (i.e., 64 degrees), and a significant decrease when these species are present (i.e., ca. 45 degrees). The observed behavior suggests that calcium ion probably has a certain chemical affinity for the active sites of the galena, which hinders the occurrence of ion exchange collector-sulfate or collector-hydroxyl to form lead xanthate (PbX2), which is the species responsible for the enhanced hydrophobicity of the mineral. On the other hand, the adverse effect of the sulfate is probably due to the formation of a layer of lead sulfate on the galena surface, which acts as a barrier that hinders the interaction of the collector with the metallic sites of the mineral lattice, thus negatively affecting the chemisorption mechanism. Likewise, the decreasing of lead concentration in solution, in equilibrium with the precipitated PbSO4 and the sulfate, limits the precipitation/coagulation of lead xanthate in the vicinity of the interface. Electrochemical measurements corroborate the proposed mechanism.