Abstract Objectives To evaluate the in vitro activities of ceftolozane/tazobactam and imipenem/relebactam against clinical isolates of Gram-negative bacilli collected in four central and northern European countries (Belgium, Norway, Sweden, Switzerland) during 2017–21. Methods Participating clinical laboratories each collected up to 250 consecutive Gram-negative isolates per year from patients with bloodstream, intraabdominal, lower respiratory tract or urinary tract infections. MICs were determined by CLSI broth microdilution and interpreted using 2022 EUCAST breakpoints. β-Lactamase genes were identified in select β-lactam-non-susceptible isolate subsets. Results Ninety-five percent of all Enterobacterales (n = 4158), 95% of ESBL-positive non-carbapenem-resistant Enterobacterales (non-CRE) phenotype Escherichia coli and 85% of ESBL-positive non-CRE phenotype Klebsiella pneumoniae were ceftolozane/tazobactam susceptible. By country, 88% (Belgium), 91% (Sweden, Switzerland) and 96% (Norway) of ESBL-positive non-CRE phenotype Enterobacterales were ceftolozane/tazobactam susceptible. Greater than ninety-nine percent of non-Morganellaceae Enterobacterales and all ESBL-positive non-CRE phenotype Enterobacterales were imipenem/relebactam susceptible. Ceftolozane/tazobactam (96%) and imipenem/relebactam (95%) inhibited most Pseudomonas aeruginosa (n = 823). Both agents retained activity against ≥75% of cefepime-resistant, ceftazidime-resistant and piperacillin/tazobactam-resistant isolates; 56% and 43% of meropenem-resistant isolates were ceftolozane/tazobactam susceptible and imipenem/relebactam susceptible, respectively. By country, 94% (Belgium), 95% (Sweden) and 100% (Norway, Switzerland) of P. aeruginosa were ceftolozane/tazobactam susceptible and 93% (Sweden) to 98% (Norway, Switzerland) were imipenem/relebactam susceptible. Carbapenemase gene carriage among Enterobacterales and P. aeruginosa isolates was generally low (<1%) or completely absent with one exception: an estimated 2.7% of P. aeruginosa ...