A randomized trial compared teicoplanin alone against flucloxacillin, with or without fusidic acid, in the treatment of serious gram-positive infections. The majority of infections involved Staphylococcus aureus or Staphylococcus epidermidis, methicillin-resistant organisms were excluded. A total of 56 patients were evaluable for efficacy, with no significant differences between treatment groups. Clinical success (cure + improvement) was achieved in 24/27 patients on teicoplanin (89%), 16 on flucloxacillin (100%) and 8/9 receiving flucloxacillin/fusidic acid (89%). Adverse events occurred in 21% of patients (7 on teicoplanin and 6 receiving flucloxacillin +/- fusidic acid). All such events resolved spontaneously or following appropriate management. It is concluded that teicoplanin monotherapy, 400 mg once daily, shows similar efficacy and tolerability to multiple daily doses of flucloxacillin, with or without fusidic acid, in the treatment of methicillin-susceptible serious gram-positive infection.