BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) constitutes a serious source of global healthcare-associated infections, and the exploration of its resistance mechanism represents an important approach to address this issue. Because current research on antibiotic resistance predominantly focuses on multidrug-resistant P. aeruginosa which is widely isolated clinically and the resistance mechanism is complicated. CRPA generally has a higher tolerance to other antibiotics than carbapenem-sensitive P. aeruginosa, yet the specific mechanism of resistance remains poorly understood. RESULTS: This study delves into the specific antibiotic resistance mechanisms of carbapenem-resistance-only P. aeruginosa (CROPA), a rare kind of pathogen that shows resistance exclusively to carbapenem antibiotics. We collected 11 clinical isolates of CROPA, performed genome sequencing. Our analysis revealed numerous amino acid mutations and premature termination of OprD expression in the CROPA strains. The insertion of IS256 element into OprD in P. aeruginosa was a novel finding. Validation via qPCR and SDS-PAGE affirmed diminished OprD expression levels. Interestingly, common carbapenemases were not detected in our study, and there was no observed upregulation of relevant efflux pumps. The expression of wild-type OprD in CROPA strains restored the sensitivity to carbapenem antibiotics. CONCLUSIONS: Compared with previous studies on MDR-CRPA, the emergence of CROPA may be directly linked to changes in OprD, while other resistance mechanisms could contribute to broader antibiotic resistance profiles. By focusing on the antibiotic resistance mechanisms of CROPA, this study illuminates the relationship between specific antibiotic resistance mechanisms and antibiotic resistance, providing a theoretical foundation for guiding clinical treatment and developing novel anti-infective agents.