Abstract Background Mycobacterium abscessus is an extensively drug resistant pathogen that causes pulmonary disease particularly in cystic fibrosis (CF) patients. Identifying direct patient-to-patient transmission of M. abscessus is critically important in directing infection control policy for the management of risk in CF patients. A variety of clinical labs have used molecular epidemiology to investigate transmission. However there is still conflicting evidence as to how M. abscessus is acquired and whether cross-transmission occurs. Recently labs have applied whole-genome sequencing (WGS) to investigate this further and in this study we investigate whether WGS can reliably identify cross-transmission in M. abscessus . Methods We retrospectively sequenced the whole genomes of 145 M. abscessus isolates from 62 patients seen at four hospitals in two countries over 16 years. Results We have shown that a comparison of a fixed number of core single nucleotide variants (SNVs) alone cannot be used to infer cross-transmission in M. abscessus but does provide enough information to replace multiple existing molecular assays. We detected one episode of possible direct patient-to-patient transmission in a sibling pair. We found that patients acquired unique M. abscessus strains even after spending considerable time on the same wards with other M. abscessus positive patients. Conclusions This novel analysis has demonstrated that the majority of patients in this study have not acquired M. abscessus through direct patient-patient transmission or a common reservoir. Tracking transmission using WGS will only realise its full potential with proper environmental screening as well as patient sampling. Key points <jats:list list-type="bullet"><jats:list-item> Whole genome sequencing should replace current molecular typing used routinely in clinical microbiology laboratories. <jats:list-item> Patient-to-patient spread of M. abscessus is not common. <jats:list-item> Environmental screening may provide a better understanding acquisition of M. abscessus infections.