BACKGROUND: Prostaglandins have mainly been used for postpartum haemorrhage (PPH) when other measures fail. Misoprostol, a new and inexpensive prostaglandin E1 analogue, has been suggested as an alternative for routine management of the third stage of labour. OBJECTIVES: To assess the effects of prophylactic prostaglandin use in the third stage of labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 January 2011). We updated this search on 25 May 2012 and added the results to the awaiting classification section. SELECTION CRITERIA: Randomised trials comparing a prostaglandin agent with another uterotonic or no prophylactic uterotonic (nothing or placebo) as part of management of the third stage of labour. The primary outcomes were blood loss 1000 mL or more and the use of additional uterotonics. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and trial quality and extracted data. MAIN RESULTS: We included 72 trials (52,678 women). Oral or sublingual misoprostol compared with placebo is effective in reducing severe PPH (oral: seven trials, 6225 women, not totalled due to significant heterogeneity; sublingual: risk ratio (RR) 0.66; 95% confidence interval (CI) 0.45 to 0.98; one trial, 661 women) and blood transfusion (oral: RR 0.31; 95% CI 0.10 to 0.94; four trials, 3519 women).Compared with conventional injectable uterotonics, oral misoprostol was associated with higher risk of severe PPH (RR 1.33; 95% CI 1.16 to 1.52; 17 trials, 29,797 women) and use of additional uterotonics, but with a trend to fewer blood transfusions (RR 0.84; 95% CI 0.66 to 1.06; 15 trials; 28,213 women). Additional uterotonic data were not totalled due to heterogeneity. Misoprostol use is associated with significant increases in shivering and a temperature of 38º Celsius compared with both placebo and other uterotonics. AUTHORS' CONCLUSIONS: Oral or sublingual misoprostol shows promising results when compared with placebo in reducing blood loss after delivery. The margin of benefit may be affected by whether other components of the management of the third stage of labour are used or not. As side-effects are dose-related, research should be directed towards establishing the lowest effective dose for routine use, and the optimal route of administration.Neither intramuscular prostaglandins nor misoprostol are preferable to conventional injectable uterotonics as part of the management of the third stage of labour especially for low-risk women; however, evidence has been building for the use of oral misoprostol to be effective and safe in areas with low access to facilities and skilled healthcare providers and future research on misoprostol use in the community should focus on implementation issues.