Among 213 Pseudomonas aeruginosa isolates collected from 10 South Korean hospitals, 57 isolates (26.8%) were carbapenem-resistant. All but three of the isolates had a relevant decrease of oprD expression. However, decreased oprD expression was also detected in five of ten carbapenem-susceptible isolates. Outer membrane protein analysis confirmed porin loss in carbapenem-resistant P. aeruginosa isolates. Based on the mutations of oprD gene sequences, carbapenem-resistant P. aeruginosa isolates could be classified into five oprD mutational groups. However, there was no difference of OprD expression or carbapenem minimum inhibitory concentrations among the five mutational groups. Among the 57 carbapenem-resistant P. aeruginosa isolates, 41 (71.9%) overexpressed efflux systems or ampC. MexAB–OprM and AmpC overexpression (56.1% and 47.4%, respectively) was prevalent and was significantly associated with carbapenem resistance. However, no synergistic effect of efflux systems and AmpC on carbapenem resistance was evident. In conclusion, combination of several mutation-driven mechanisms leading to OprD inactivation and overexpression of efflux systems was the main carbapenem resistance mechanism, but acquisition of a transferable resistance determinant such as metallo-β-lactamase could be problematic in clinical settings in South Korea.