BACKGROUND: Postpartum haemorrhage is a leading cause of maternal morbidity and mortality. Active management of the third stage of labour, including use of a uterotonic agent, has been shown to reduce blood loss. Misoprostol (a prostaglandin E1 analogue) has been suggested for this purpose because it has strong uterotonic effects, can be given orally, is inexpensive, and does not need refrigeration for storage. We did a multicentre, double-blind, randomised controlled trial to determine whether oral misoprostol is as effective as oxytocin during the third stage of labour. METHODS: In hospitals in Argentina, China, Egypt, Ireland, Nigeria, South Africa, Switzerland, Thailand, and Vietnam, we randomly assigned women about to deliver vaginally to receive 600 microg misoprostol orally or 10 IU oxytocin intravenously or intramuscularly, according to routine practice, plus corresponding identical placebos. The medications were administered immediately after delivery as part of the active management of the third stage of labour. The primary outcomes were measured postpartum blood loss of 1000 mL or more, and the use of additional uterotonics without an unacceptable level of side-effects. We chose an upper limit of a 35% increase in the risk of blood loss of 1000 mL or more as the margin of clinical equivalence, which was assessed by the confidence interval of the relative risk. Analysis was by intention to treat. FINDINGS: 9264 women were assigned misoprostol and 9266 oxytocin. 37 women in the misoprostol group and 34 in the oxytocin group had emergency caesarean sections and were excluded. 366 (4%) of women on misoprostol had a measured blood loss of 1000 mL or more, compared with 263 (3%) of those on oxytocin (relative risk 1.39 [95% CI 1.19-1.63], p<0.0001). 1398 (15%) women in the misoprostol group and 1002 (11%) in the oxytocin group required additional uterotonics (1.40 [1.29-1.51], p<0.0001). Misoprostol use was also associated with a significantly higher incidence of shivering (3.48 [3.15-3.84]) and raised body temperature (7.17 [5.67-9.07]) in the first hour after delivery. INTERPRETATION: 10 IU oxytocin (intravenous or intramuscular) is preferable to 600 microg oral misoprostol in the active management of the third stage of labour in hospital settings where active management is the norm.