BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality. Uterotonics are the mainstay of PPH prevention. OBJECTIVES: To compare the efficacy of misoprostol and oxytocin for the prevention of PPH and to evaluate the trustworthiness of these randomised controlled trials (RCTs). SEARCH STRATEGY AND SELECTION CRITERIA: Seven databases were searched for peer-reviewed literature meeting the inclusion criteria of RCTs comparing misoprostol and oxytocin for the prevention of PPH. DATA COLLECTION AND ANALYSIS: Data were collected by two independent reviewers. Individual participant data (IPD) were meta-analysed for outcomes PPH ≥ 500 and ≥ 1000 mL. RCTs that did not share IPD were classified as trustworthy or not, and aggregate data were meta-analysed according to trustworthiness. MAIN RESULTS: Of 79 eligible RCTs, 10 (12.7%) provided IPD, of which 6 were included. Analysis of IPD showed PPH ≥ 500 mL to be significantly higher in the misoprostol than in the oxytocin group (2022 participants, aOR 1.84, 95% CI 1.43-2.34). For PPH ≥ 1000 mL, analysis of IPD showed that misoprostol and oxytocin were comparable (2022 participants, OR 1.14, 95% CI 0.68-1.91). Of the 69 studies that did not provide IPD, 23 (33.3%) were assessed as trustworthy. Analysis of trustworthy data (IPD and 23 aggregate data RCTs) showed no difference between misoprostol and oxytocin for PPH ≥ 500 mL (24 334 participants, OR 1.01, 95% CI 0.69-1.49), while misoprostol was associated with a significantly increased risk of PPH ≥ 1000 mL compared to oxytocin (25 249 participants, OR 1.36, 95% CI 1.16-1.59). CONCLUSIONS: Of 79 RCTs comparing misoprostol and oxytocin for the prevention of PPH, 36.7% met trustworthiness criteria. Oxytocin is comparable to misoprostol for preventing PPH and may be superior for preventing severe PPH.