Contemporary clinical isolates and challenge strains of Pseudomonas aeruginosa were tested by four automated susceptibility testing systems (BD Phoenix, MicroScan WalkAway, Vitek, and Vitek 2; two laboratories with each) against six broad-spectrum beta-lactams, and the results were compared to reference broth microdilution (BMD) and to consensus results from three validated methods (BMD, Etest [AB Biodisk, Solna, Sweden], and disk diffusion). Unacceptable levels of error (minor, major, and very major) were detected, some with systematic biases toward false susceptibility (piperacillin-tazobactam and imipenem) and others toward false resistance (aztreonam, cefepime, and ceftazidime). We encourage corrective action by the system manufacturers to address test biases, and we suggest that clinical laboratories using automated systems should consider accurate alternative methods for routine use.