To compare the effectiveness and safety of the oxytocin antagonist atosiban with conventional beta-adrenergic agonist (beta-agonist) therapy in the treatment of preterm labour.Three multinational, multicentre, double-blind, randomised, controlled trials. Setting Hospitals in Australia, Canada, Czech Republic, Denmark, France, Israel, Sweden, and the UK.Women diagnosed with preterm labour at 23-33 completed weeks of gestation.Seven hundred and forty-two women were randomised; 733 received atosiban (n = 363; intravenous (iv) bolus dose of 6.75 mg, then 300 microg/minute iv. for 3h and 100 microg/min iv thereafter) or beta-agonist (n = 379; ritodrine, salbutamol or terbutaline iv; dose titrated) for at least 18h and up to 48 hours. Uterine contraction rate, cervical dilatation and effacement were used to assess progression of labour. An all patients treated analysis, using the Cochran-Mantel-Haenszel test, was performed.Tocolytic effectiveness was assessed in terms of the number of women undelivered after 48 hours and seven days. Safety was assessed in terms of maternal side effects and neonatal morbidity.There were no significant differences between atosiban and beta-agonists in delaying delivery for 48h (88.1% vs 88.9%; P = 0.99) or seven days (79.7% versus 77.6%; P = 0.28). Tocolytic effectiveness was also similar in terms of mean [SD] gestational age at delivery (35.8 [3.9] weeks vs 35.5 [4.1] weeks) and mean [SD] birthweight (2,491 [813] g versus 2,461 [831] g). Maternal side effects, particularly cardiovascular adverse events (8.3% vs 81.2%, P < 0.001), were reported more frequently in women given beta-agonists, resulting in more treatment discontinuations due to side effects (1.1% vs 15.4%, P = 0.0001). No statistical differences in neonatal/infant outcomes were observed with either study medication.In the largest study of tocolytic therapy to date, atosiban was comparable in clinical effectiveness to conventional beta-agonist therapy, but was associated with fewer maternal cardiovascular side effects. We conclude that atosiban has clinical advantages over current tocolytic therapy.