OBJECTIVES: To evaluate the antimicrobial susceptibility and resistance mechanisms to ß-lactams among Enterobacter cloacae and Citrobacter freundii from United States medical centres. METHODS: 2571 E. cloacae and 1008 C. freundii species complex isolates were consecutively collected from 77 medical centres and susceptibility tested by broth microdilution method. Isolates displaying MIC values ≥16 mg/L for ceftazidime or ≥2 mg/L for cefepime (n = 914) were tested for ß-lactamase-encoding genes using whole genome sequencing. RESULTS: Overall susceptibility to ceftazidime and cefepime were 73.9% and 91.2% among E. cloacae and 74.2% and 93.5% among C. freundii, respectively. Sixty-three isolates harboured a carbapenemase gene, including 56 bla KPC, 2 bla NMC-A, and 5 metallo-ß-lactamase genes. Among non-carbapenemase producers, 121 isolates had at least one ESBL-encoding gene, mainly bla SHV (81) or bla CTX-M (61), and 15 had a transferable AmpC gene, mainly bla DHA-1 (8) or bla FOX-5 (6). Carbapenemase, ESBL, or transferable AmpC-encoding genes were not identified among 718 of 914 (78.6%) isolates sequenced. The most active agents against isolates with a decreased susceptibility to ceftazidime and/or cefepime were ceftazidime/avibactam (MIC50/90, 0.5/1 mg/L; 99.3% susceptible), amikacin (MIC50/90, 1/4 mg/L; 99.5% susceptible), and meropenem (MIC50/90, 0.06/0.5 mg/L; 92.9% susceptible). The isolates resistant to ceftazidime/avibactam were the five MBL producers and one E. cloacae isolate with a reduced expression of OmpF and overexpression of AcrAB-TolC. CONCLUSIONS: Hyperproduction of chromosomal AmpC appears to be the most common mechanism of resistance to ceftazidime and/or cefepime in E. cloacae and C. freundii. Ceftazidime/avibactam remained highly active against most isolates showing decreased susceptibility to ceftazidime and/or cefepime.