Pseudomonas aeruginosa (PA) is an opportunistic pathogen causing chronic lung infections in mechanically ventilated patients, people with cystic fibrosis and chronic obstructive pulmonary diseases. Recently, it has been shown that a strain of PA with a mutated OprD porin (oprD mutant) had increased fitness and virulence in mouse models of intestinal colonization and acute pneumonia. As carbapenems use the OprD porin to enter the bacterial cytoplasm, mutations leading to loss of the OprD porin confer carbapenem resistance, one of the treatments of last resort for antibiotic-resistant PA. The aim of our study was to assess the virulence of a PA oprD mutant on Human Airway Epithelia (HAE). Fully differentiated epithelia were obtained from primary cells cultured at the air-liquid interface that were infected with carbapenem-susceptible WT and a carbapenem-resistant oprD mutant PA strain. The dynamics of epithelial destruction was studied using time-lapse microscopy. Epithelia were damaged by the oprD mutant PA strain after 40.9 ± 2.7 h of exposure vs 54.7 ± 3.9 h for the WT PA strain (P=0.019), indicating a higher virulence of the oprD mutant strain. This higher virulence was due to enhanced multiplication of the oprD mutant during infection. RNA sequencing and transcriptomic analyses to compare the gene expression of the 2 strains grown on the HAE revealed an overexpression in the oprD mutant of the NAD(P)H quinone oxidoreductase NQO (EDGE test, fold change > 2, P< 0.05), a key player in the response of P. aeruginosa to antibacterial oxidative stress. Thus, our findings showed that a PA oprD carbapenem-resistant mutant is more destructive to the HAE owing to a better response to oxidative stress. This study will extend our knowledge of PA pathogenesis and may form the basis for designing effective interventions to reduce epithelial cell destruction in chronic PA infection.