This work aims at optimizing sludge pretreatment by non-isothermal sonication, varying frequency, US power (PUS) and intensity (IUS varied through probe size), as well as hydrostatic pressure and operation mode (continuous vs. sequential - or pulsed - process). Under non isothermal sonication sludge solubilization results from both ultrasound disintegration and thermal hydrolysis which are conversely depending on temperature. As found in isothermal operation: - For a given specific energy input, higher sludge disintegration is still achieved at higher PUS and lower sonication time. - US effects can be highly improved by applying a convenient pressure. - 12 kHz always performs better than 20 kHz. Nevertheless the optimum pressure depends not only on PUS and IUS, but also on temperature evolution during sonication. Under adiabatic mode, a sequential sonication using 5 min US-on at 360 W, 12 kHz, and 3.25 bar and 30 min US-off gives the best sludge disintegration, while maintaining temperature in a convenient range to prevent US damping.