Novobiocin and rifampicin were evaluated in vitro as a possible new antibiotic combination against methicillin-resistant Staphylococcus aureus. An evaluation of 20 strains of methicillin-resistant Staph. aureus using microdilution checkerboard techniques at 10⁵ cfu/ml showed neither synergy nor antagonism between novobiocin and rifampicin or between vancomycin and rifampicin. Agar surface inoculation of six strains of methicillin-resistant Staph. aureus showed increased synergy with increased inocula (10⁶−10⁹ cfu) for novobiocin plus rifampicin compared to vancomycin plus rifampicin. Time-kill curves showed indifference at 6 h for all combinations, whereas, at 24 and 48 h, they generally showed indifference, occasionally synergy, but never antagonism. The ‘synergy’ between novobiocin and rifampicin at higher inocula of methicillin-resistant Staph. aureus appears to be due to prevention of emergence of resistant organisms and may have clinical relevance. The combination of novobiocin-rifampicin merits further investigation.