Carbapenem-resistant Enterobacterales are a major public health concern worldwide. They have been included in the critical priority group of the WHO annual pathogen list given their relevance in terms of burden, transmissibility, treatability, preventability, and research into new treatments [1]. The most common mechanism of carbapenem resistance is the production of carbapenemases mainly due to the global spread of five enzymes: KPC (Ambler class A), metallo-β-lactamases (Ambler class B, e.g., NDM, VIM, and IMP), and OXA-48-like (Ambler class D) [2,3]. Knowledge of the type of carbapenemase is of paramount importance to guide antibiotic therapy, especially in view of the large number of newly or soon-to-be introduced active drugs [[4], [5], [6]]. The IDSA guidelines currently recommend ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam as preferred treatment options for infections caused by KPC-producing Enterobacterales; ceftazidime/avibactam for those caused by OXA-48-like-producing Enterobacterales; and ceftazidime/avibactam in combination with aztreonam or cefiderocol as monotherapy for infections sustained by metallo-β-lactamases-producing Enterobacterales [7]. In recent years, however, given the horizontal gene transfer capacity of carbapenemase-encoding gene located on plasmids, the gradual emergence of multi-carbapenemases producers among Enterobacterales complicated the epidemiological and clinical scenario [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]], generating interest in the development of new treatment strategies [10,21]. Carriage of more than one carbapenemase may in fact provide a broader antibiotic resistance profile, especially when metallo-β-lactamases co-occur with serine-carbapenemases, with the therapeutic armamentarium in these cases limited to aztreonam/avibactam and possibly cefiderocol [[22], [23], [24]]. Although multi-carbapenemases producing Enterobacterales (MCP-EB) are not common in Europe, data on these organisms and associated infections are fragmentary, often based on a few anecdotal reports [11,17,18,20]. Recognizing the challenges in developing effective strategies to keep this new and worrying phenomenon at bay, this study set out to investigate the clinical characteristics and mortality of patients with MCP-EB, providing a real-world scenario of antimicrobial susceptibility profiles, antibiotic management and clinical outcomes.