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• Gram-positive pathogens are a major cause of infections. • The dissemination of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) has reduced the therapeutic options. • Antimicrobial activity of dalbavancin and other comparators was evaluated against recent clinical isolates of Gram-positive pathogens from several European countries and Russia. • The activity of dalbavancin against Gram-positive pathogens, including MRSA, was high [ minimum concentration inhibiting 90% of isolates tested (MIC 90) ≤0.12 mg/L for all isolates except vanA- harbouring enterococci, which had MIC 90 >2 mg/L] and remained unchanged over the years. • MRSA circulating inside and between countries revealed considerable clonal heterogeneity • These data support the efficacy of dalbavancin against Gram-positive pathogens, including MRSA and uncommon species. Gram-positive pathogens remain a major cause of healthcare- and community-associated infections. In particular, the dissemination of methicillin-resistant staphylococci, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), have significantly reduced the therapeutic options, making the management of these infections even more challenging. Dalbavancin is a second-generation lipoglycopeptide approved for the treatment of moderate to severe acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive organisms, showing a bactericidal effect and a low propensity towards the selection of resistance over time. To evaluate the antimicrobial activity of dalbavancin and other comparators against recent clinical isolates of Gram-positive pathogens obtained from different sources and from several European countries, including countries of Southern and Eastern Europe, and Russia, where resistance rates are typically high. This study also aimed to describe the clonal relationship of MRSA strains circulating in Southern and Eastern Europe and Russia. In total, 1478 isolates were collected. Study results demonstrated the excellent and stable activity of dalbavancin against Gram-positive microorganisms, including MRSA. Interestingly, dalbavancin has retained unaltered minimum inhibitory concentration (MIC 50 and MIC 90) values over the years, and seems to have a low propensity towards the selection of resistance. These data support the potential efficacy of dalbavancin against Gram-positive bacteria and uncommon Gram-positive pathogens in patients with ABSSSIs. Of note, few coagulase - negative staphylococci (CoNS) isolates were resistant to dalbavancin and susceptible to vancomycin, highlighting the importance of testing for susceptibility to dalbavancin before its administration for CoNS infections. [ABSTRACT FROM AUTHOR]