This study represents one of the most comprehensive characterisations of the anaerobic digestion (AD) microbiome with 80 samples from 45 different large-scale reactors in three coun-tries. Technical, chemical and taxonomic data was thoroughly collected, analyzed and correlated to identify the main drivers of AD processes. Our results showed that MBA03,Proteiniphilum, a member ofDethiobacteraceae, andCaldicoprobacterwere present in all the samples, whileMeth-anosarcinawas the most abundant and prevalent archaea. Two distinct bacterial clusters were iden-tified by correlating microbial abundances. One was correlated with hydrogenotrophic and the other with acetoclastic methanogenesis. Organic acids, ammonia, nitrogen, COD and the trace el-ements Fe, Mo, and the macro nutrient P had the greatest impact on AD microbiomes. Temperature, reactor type and substrate also influenced the formation of a specialized microbial community. Overall, this work sheds light on the microbial key players involved in AD and evaluates how they are affected by technical and chemical parameters.HighlightsGeneration of a holistic dataset of chemical, taxonomic and technical parameters of 80 large-scale anaerobic digestion systems.Identification of a core microbiome comprising MBA03,Proteiniphilum, an uncultured or-ganism from theDethiobacteraceaefamily, and theCaldicoprobacterfamily.Identification of the main influencing parameters that determine the occurrence and non-occurrence of specific genera.Correlation of bacterial taxa with hydrogenotrophic and/or acetoclastic archaea.