ABSTRACT Combination therapy is an attractive option for the treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections; however, limited data are available on combinations with ceftolozane-tazobactam (C-T). The in vitro pharmacodynamic chemostat model was employed to compare human-simulated exposures of C-T at 3 g every 8 h alone or in combination with amikacin at 25 mg/kg of body weight daily or colistin at 360 mg daily against four MDR P. aeruginosa isolates. C-T alone resulted in 24-h changes in the number of CFU of −0.02 ± 0.21, −1.81 ± 0.55, −1.44 ± 0.40, and +0.62 ± 0.05 log ₁₀ CFU/ml against isolates with C-T MICs of 4, 4, 8, and 16 μg/ml, respectively. Amikacin and colistin monotherapy displayed various results. The addition of amikacin to C-T resulted in −2.00 ± 0.23 ( P < 0.001, additive)-, −1.50 ± 0.83 ( P = 0.687, indifferent)-, −2.84 ± 0.08 ( P = 0.079, indifferent)-, and −2.67 ± 0.54 ( P < 0.001, synergy)-log ₁₀ CFU/ml reductions, respectively. The addition of colistin to C-T resulted in −3.02 ± 0.22 ( P < 0.001, additive)-, −3.21 ± 0.24 ( P > 0.05, indifferent)-, −4.6 ± 0.11 ( P = 0.002, synergy)-, and −3.01 ± 0.28 ( P < 0.001, synergy)-log ₁₀ CFU/ml reductions, respectively, against the MDR P. aeruginosa isolates with these MICs. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 h, with C-T plus amikacin or colistin were observed against 3 out of 4 MDR P. aeruginosa strains tested, particularly those strains that were intermediate or resistant to C-T. Further studies assessing combination regimens containing C-T against MDR P. aeruginosa are warranted.