We investigated whether the use of misoprostol plus oxytocin in the active management of the third of stage of labour (AMTSL) would reduce the rate of primary postpartum haemorrhage (PPH) compared with intramuscular oxytocin alone. This was a multicentre, double-blind, placebo-controlled, randomised trial where 1036 pregnant women, in addition to intramuscular oxytocin (10 IU) in the third stage of labour, randomly received either 400 µg sublingual misoprostol (519 women) or a placebo (517 women). The primary outcome measure was the mean blood loss (MBL) within 1 h of delivery. The trial was registered with ClinicalTrials.gov (NCT02424201). The MBL in the oxytocin plus misoprostol group was 229.73 ± 108.12 compared to 274.58 ± 121.09 in the oxytocin plus placebo group (t = 6.289, p < .001). Twenty-eight (5.4%) women in the misoprostol group had a blood loss ≥500 ml versus 39 (7.5%) women in the placebo group (risk-ratio [RR] − 0·72, 95%CI 0.45–1.14; p = .1616). The combination of misoprostol with oxytocin in the AMTSL reduces MBL post-delivery but is not superior to oxytocin alone in the reduction of the rate of PPH. IMPACT STATEMENT What is already known on this subject? The routine use of 10IU of intramuscular oxytocin in the active management of the third stage of labour reduces the rates of postpartum haemorrhage. What do the results of this study add? The addition of 400ug of sublingual misoprostol to the routine use of 10IU of intramuscular oxytocin in the active management of the third stage of labour reduces mean blood loss when compared with intramuscular oxytocin alone, but is not better in reducing the rates of postpartum haemorrhage. What are the implications of these findings for clinical practice and/or further research? Routine use of misoprostol as adjuncts to the active management of the third stage of labour does not reduce the rate of PPH.