Flotation separation of smithsonite from calcite is difficult due to their similar surface properties. In the present study, a reagent scheme of depressant calcium lignosulphonate (CLS) and collector benzyl hydroxamic acid (BHA) was introduced in the flotation of smithsonite from calcite. Microflotation tests revealed that the efficient flotation of smithsonite from calcite could only be obtained with the addition order of BHA before CLS, which was opposite to the widely-used order that adding depressant prior to the collector. The zeta potential measurements indicated that BHA selectively adsorbed onto smithsonite surface, then not allowed the CLS adsorption onto the smithsonite surface rather than calcite surface because of the steric hindrance, thereby the smithsonite surface remained hydrophobic while calcite sur-face became more hydrophilic after the addition of CLS. As a result, the calcite flotation was completely depressed while the smithsonite flotation recovery was still in high value, leading to the optimal flotation separation performance.