Abstract Background Aztreonam/avibactam is a novel β-lactam/β-lactamase inhibitor (BL/BLI) combination active against carbapenem-resistant Enterobacterales (CRE), including MBL-producing isolates. In May 2024, EUCAST published Enterobacterales breakpoints for aztreonam/avibactam. This study aimed to assess the performance of commercially available disc diffusion (DD) against broth microdilution (BMD) using the latest EUCAST breakpoints. Methods We tested 278 CRE causing infections in 17 Greek ICUs between 2021 and 2023, using 30/20 μg aztreonam/avibactam discs and BMD according to EUCAST methodology and EUCAST version 15.0 breakpoints. Results Most isolates were identified as Klebsiella pneumoniae (97.8%), and 98.9% produced carbapenemases, including 46.4% KPC, 20.1% NDM, 5.4% VIM and 27% multiple carbapenemases. Using BMD, 94.2% of isolates were susceptible to aztreonam/avibactam. Conversely, using DD, 66.9% were susceptible, 33.1% resistant and 27% within the area of technical uncertainty (ATU). Most isolates in the ATU were KPC-producing (68%) or KPC and MBL-producing (29.3%). All isolates in the ATU (22–24 mm) tested susceptible by BMD (MIC ≤ 4 mg/L). One isolate exhibited resistance by DD (20 mm), but was susceptible by BMD. Categorical agreement (CA) was 72.7%, with 29% major errors (MEs) and 0% very major errors (VMEs). Using a breakpoint of 22 mm, CA, ME and VME were 99.6%, 0.4% and 0%, respectively. Conclusions Aztreonam/avibactam showed potent in vitro activity against MBL- and KPC-producing Enterobacterales. Using the 2025 EUCAST breakpoint, all isolates in the ATU tested susceptible by BMD, leading to high MEs of the DD method. A 22 mm breakpoint would have corrected this discrepancy in our cohort.