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The organic fraction of municipal solid waste (OFMSW) is widely recognized as a possible substrate for anaerobic digestion processes. However, the heterogeneity of this matrix and the presence of slowly biodegradable compounds can slow down anaerobic digestion and reduce its performance. This study compares the effectiveness of different thermal pre-treatments in increasing OFMSW anaerobic digestibility. Thermal pre-treatments were compared with OFMSW shredding, considered as the minimum pre-treatment required in order to reduce particles size of the OFMSW. The pre-treatments were performed in autoclave (121 °C and 1.4 bar for 20 min) or in an ad hoc hydrolysis reactor designed for the experimental trial (140 °C and 7 bar for 30 min) with air or nitrogen as gas phase. The thermal pre-treatments affected methane yield (NmLCH4/gVS), depending on the pre-treatment strategy, with autoclaving allowing for an 80% increase with respect to the control run, and leading to a methane yield of 476 ± 194 NmLCH4/gVS. The pre-treatments in the hydrolysis reactor caused a loss of organic matter (due to its volatilization) reducing the organic loading rate of the digester. Nevertheless, the digester performance in terms of COD (chemical oxygen demand) and VSS (volatile suspended solid) removal showed limited differences among the pre-treatments applied and ranged on average 79–94%. [ABSTRACT FROM AUTHOR]