This study evaluated the activity of tigecycline combined with imipenem, amikacin, and ciprofloxacin against clinical isolates of multidrug-resistant Klebsiella pneumoniae and Escherichia coli co-producing extended-spectrum β-lactamases and acquired AmpC β-lactamases. Broth microdilution tests were performed for cefotaxime, ceftazidime, cefepime, imipenem, amikacin, ciprofloxacin, and tigecycline. Time-kill synergy studies were tested for tigecycline plus imipenem, tigecycline plus amikacin, and tigecycline plus ciprofloxacin. Imipenem (MIC(90) = 1 μg/ml for both K. pneumoniae and E. coli) and tigecycline (MIC(90) = 2 μg/ml for K. pneumoniae and 1 μg/ml for E. coli) were the most potent agents. Combination studies with tigecycline plus imipenem resulted in synergy against 18 K. pneumoniae and 3 E. coli isolates; tigecycline plus amikacin yielded synergy against 8 K. pneumoniae and 3 E. coli isolates; tigecycline plus ciprofloxacin yielded synergy against 7 K. pneumoniae and 2 E. coli isolates. No antagonism was observed with any combination. In the present study, imipenem, amikacin, and ciprofloxacin led to indifferent and some synergistic effects in combination with tigecycline, and none of them demonstrated antagonistic effects.