Community-acquired and nosocomial infections caused by multidrug-resistant Gram-positive pathogens continue to increase in prevalence and have become a serious problem in many parts of the world. BAL9141 is a member of the class of parenteral pyrrolidinone-3-ylidenemethyl cephalosporins, and has a broad spectrum of activity. In the current study, BAL9141 was tested against a large number (n = 2263) of recent isolates from various international surveillance programmes including 1097 Gram-positive strains. Susceptibility to (S) and activity of (mg/L) to BAL9141, based on proposed breakpoints (MIC50/MIC90/% S) were as follows: methicillin-susceptible Staphylococcus aureus (0.5/0.5/100%), methicillin-resistant S. aureus (MRSA) (1/2/100%), methicillin-susceptible coagulase-negative staphylococci (CoNS) (0.12/0.25/100%), methicillin-resistant CoNS (MR-CoNS) (1/2/100%), Streptococcus pneumoniae (≤0.015/0.25/100%), viridans group streptococci (0.03/0.5/99%), β-haemolytic streptococci (≤0.015/≤0.015/100%), Enterococcus faecalis (0.5/16/90%), Enterococcus faecium (>32/>32/22%), Haemophilus influenzae (0.06/0.06/100%), Moraxella catarrhalis (0.06/0.5/100%), Neisseria gonorrhoeae (0.03/0.06/100%) and Neisseria meningitidis (≤0.002/0.004/100%). BAL9141 susceptibility at ≤4 mg/L (100% S) surpassed that of ceftriaxone (CRO; 1% S) and quinupristin/dalfopristin (Q-D; 92% S) against MRSA and MR-CoNS (CRO 0.9% S; Q-D 94% S). All S. pneumoniae were inhibited by BAL9141 at ≤1 mg/L compared with CRO (90% S) and levofloxacin (LVX; 98% S). Susceptibility rates for viridans group streptococci to BAL9141 (>98%) were also higher than to CRO (86%) and LVX (96%). BAL9141 demonstrated excellent activity against most species of wild-type enteric bacilli, with ≥95% of isolates being susceptible; however, only modest activity was observed for BAL9141 against non-fermentative Gram-negative species and ESBL-producing Escherichia coli or Klebsiella pneumoniae. BAL9141 demonstrated excellent activity against many tested pathogens displaying various resistance phenotypes, and should be particularly valuable in the treatment of MRSA as well as for drug-resistant streptococci, while maintaining a spectrum resembling a ‘third-generation’ cephalosporin against other clinically important species.