Introduction: Pseudomonas aeruginosa AUST-03 (ST242) has been reported to cause epidemics in cystic fibrosis (CF) patients from Tasmania and Australia and has been associated with multidrug resistance and increased morbidity and mortality. Here, we report epidemic P. aeruginosa (AUST-03) strains in South African CF patients at a public academic hospital detected during a previous study and characterise the resistomes. Methods: The P. aeruginosa AUST-03 (ST242) strains were analysed with whole genome sequencing using the Illumina NextSeq2000 platform. Raw sequencing reads were processed using the Jekesa pipeline and multi-locus sequence typing and resistome characterisation was performed using public databases. Core single nucleotide polymorphism phylogenies were performed on P. aeruginosa ST242 strains from the study and from public databases. Antibiotic susceptibility testing was performed using the disk diffusion and broth microdilution techniques. Results: A total of 11 P. aeruginosa AUST-03 strains were isolated from two children with CF who had pulmonary exacerbations. The majority of the P. aeruginosa AUST-03 strains (8/11) were multidrug resistant (MDR) or extensively drug resistant; and the multidrug efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, MexXY-OprM were the most clinically relevant antibiotic resistance determinants and were detected in all of the strains. The P. aeruginosa AUST-03 (ST242) study strains were most closely related to strains from Canada, China, Denmark and Slovenia. Conclusion: Epidemic MDR P. aeruginosa strains are present at South African public CF clinics and need to be considered when implementing patient segregation and infection control strategies to prevent further spread and outbreaks.