Vancomycin-resistant Enterococcus faecium (VRE) belonging to sequence type 80 (ST80) have been successfully disseminating in hospital settings. This study aimed to explore whole-genome sequencing (WGS)-based approaches in epidemiological typing of VRE by investigating a collection of ST80 strains. In total, 41 VRE ST80 isolates in three suspected transmission chains were subjected to WGS. The genetic relationship of the isolates was analysed by core genome multilocus sequence typing (cgMLST) and single nucleotide polymorphism (SNP)-based typing. The published genome sequence of a predominant ST80 clone in Copenhagen was also included in the analyses. Group 1 isolates (n=10) were recovered in the same geographic area, including two isolates from an outbreak of vanA genotype. Group 2 isolates (n=4) were detected from another outbreak. Group 3 consisted of 3 non-outbreak isolates and 24 representative isolates from an outbreak of vanB genotype. Our findings indicated ≥24 allelic difference and >16 SNPs as the cut-off for excluding VRE strains from an outbreak. cgMLST identified >200 differing alleles between genomes of the Copenhagen clone and outbreak strains in this study. Our findings also demonstrated that SNP analysis was not suitable for typing samples from different groups, even with the same ST, owing to lack of an optimal reference genome. cgMLST and SNPs provided comparable epidemiological discrimination for isolates with a suspected transmission chain. For diverse isolates, SNP analysis could be suboptimal. An approach applying cgMLST as the first-line typing method and SNPs as a complementary tool is suggested.