Hydrodynamic cavitation systems have shown considerable promise for wastewater treatment. These systems are also used as a sludge pretreatment device to increase treatment efficiency of anaerobic sludge digestion systems. Although there are some literature related to disintegration of waste-activated sludge by hydrodynamic cavitation, effects of some operational variables in an orifice-based system, such as cavitation number and orifice diameter on sludge solubilization efficiency, are missing. In this study, waste-activated sludge that originated from a food processing facility was disintegrated mechanically on a laboratory scale using an orifice-based hydrodynamic cavitator. Use of NaOH, Ca(OH)(2), and H2O2 together with hydrodynamic cavitation was also evaluated. Results showed that after 150min of cavitation, disintegration degrees of 32% to 60% were obtained. Based on results, optimum cavitation number and orifice diameter selected for disintegration of waste-activated sludge were 0.2 and 3mm, respectively. Enhanced solubilization was achieved in the case of hydrodynamic cavitation combined with chemical addition. The best results for the disintegration of solids and organic carbon release in terms of soluble chemical oxygen demand (SCOD) were obtained for the combined system of H2O2 addition with a dose of 20mg/L and hydrodynamic cavitation. According to biochemical methane potential test (BMP) results, 20% to 89% higher biogas production was observed in disintegrated sludges comparing to raw sludge.