The efficacy, safety and tolerability of linezolid was compared with teicoplanin in a randomized, controlled, open-label, multicentre study of 430 patients with suspected or proven Gram-positive infection. Patients received intravenous (iv) +/- oral linezolid 600 mg every 12 h (n = 215) or iv or intramuscular teicoplanin (n = 215) for up to 28 days. Clinical outcomes in the intent-to-treat (ITT) and clinically-evaluable populations and microbiological success rates in microbiologically evaluable patients were assessed at follow-up (test of cure). Investigator assessed clinical cure rates at end of treatment (EOT) in ITT patients treated with linezolid (95.5%) were superior to those of teicoplanin (87.6%) for all infections combined, indicating a 7.9% statistically significant treatment advantage for linezolid (P = 0.005, 95% CI: 2.5, 13.2). Clinical cure rates by baseline diagnosis were consistently higher at EOT for the linezolid versus teicoplanin groups with skin and soft tissue infection (96.6% versus 92.8%), pneumonia (96.2% versus 92.9%) and bacteraemia (88.5% versus 56.7%). The 31.8% treatment advantage in bacteraemic patients (but not for those seen in the other infection categories) for linezolid-treated patients was statistically significant (P = 0.009, 95% CI: 10.2, 53.4). Bacterial eradication rates for linezolid exceeded those of teicoplanin for all infection sites combined but this did not reach statistical significance (81.9% versus 69.8%, respectively; P = 0.056). Adverse event rates were similar between the treatment groups, were mild to moderate in severity, and resolved quickly following treatment. The linezolid group experienced a higher incidence of drug related adverse events (30% versus 17%; P = 0.002), and notably of gastrointestinal effects (13.0% versus 1.9%, P = 0.001). However, antibiotic discontinuation rates as a result of drug related adverse events were similar (4.7% in the linezolid group versus 3.7%). Linezolid was clinically superior to teicoplanin in the treatment of Gram-positive infections.