Abstract: The effect of hydrodynamic cavitation on removal of refractory hydrophilic and hydrophobic pollutants and their mixtures, using a self-developed hydrodynamic cavitation reactor composed of a Venturi tube, multi-orifice plates or their combinations, was studied experimentally and systemically. First, three types of Venturi tubes with different relative throat lengths were designed and tested, and their effects on the degradation rates of hydrophobic pollutants were concluded. Then, four types of multi-orifice plates with checkerboard arrangement and staggered arrangement of triangular orifices were examined, and the effects of different numbers and sizes of the orifices on removal of hydrophilic pollutants were studied. Finally, combinations of Venturi tubes with multi-orifice plates were adopted to treat hydrophilic and hydrophobic mixtures, and their degradation rates were measured and compared. Our measurements show that relative throat length is a key factor in the degradation of hydrophobic pollutants and has an optimal value of L/R = 40. And increasing orifice number or reducing orifice size is favorable to degradation of hydrophilic pollutants, and a hydraulic condition for more effective cavitation can be achieved through combining a Venturi tube with the orifice plates of checkerboard arrangement. In addition, cavitation intensity can be improved by increasing flow velocity, reducing cavitation number, extending treatment time, or using suitable initial concentration of wastewater.