a b s t r a c tAt industrial scale, thermal hydrolysis is the most used process to enhance biodegradability of the sludge produced in wastewater treatment plants. Through statistically guided Box-Behnken experimental design, the present study analyses the effect of TH as pre-treatment applied to activated sludge. The selected process variables were temperature (130-180 C), time (5e50 min) and decompression mode (slow or steam-explosion effect), and the parameters evaluated were sludge solubilisation and methane production by anaerobic digestion. A quadratic polynomial model was generated to compare the process performance for the 15 different combinations of operation conditions by modifying the process variables evaluated. The statistical analysis performed exhibited that methane production and solubility were significantly affected by pre-treatment time and temperature. During high intensity pre-treatment (high temperature and long times), the solubility increased sharply while the methane production exhibited the opposite behaviour, indicating the formation of some soluble but non-biodegradable materials. Therefore, solubilisation is not a reliable parameter to quantify the efficiency of a thermal hydrolysis pre-treatment, since it is not directly related to methane production. Based on the operational parameters optimization, the estimated optimal thermal hydrolysis conditions to enhance of sewage sludge digestion were: 140e170 C heating temperature, 5e35min residence time, and one sudden decompression.