The performance of hydroxamic polyacrylamide (HPAM) in mineral flotation was tested on the samples of calcite, diaspore and pyrite. It is found that HPAM expresses intensive depression on pyrite and can be used as effective depressants for pyrite. The depression mechanism of HPAM to pyrite was investigated by the determination of contact angle, zeta potential, adsorptive capacity for collectors and infrared spectrum. A lower contact angle, more negative zeta potential, less xanthate adsorptive capacity, and the formation of chemical bonding were determined, which reveals that the strong chemical interactions exist between HPAM and pyrite surface. The group electronegativity of HPAM was calculated to explain the differences of interaction between reagent and minerals.