Consecutive intra-umbilical vein injection of misoprostol and intravenous sulprostone in the management of retained placenta (RP). The general accepted treatment of RP is manual removal of the placenta (MRP), but medical intervention protocols were suggested. We evaluate a protocol of using intra-umbilical vein injection of misoprostol followed, if necessary, by intravenous sulprostone. A reduction in the need for MRP and less blood loss was expected. Cohort A (1 January 2007 to 31 September 2008), managed by an expectative protocol including active management of the third stage of labor and if necessary MRP performed 60 min after birth of the baby, was compared with cohort B (1 April 2009 to 31 December 2010) managed by medical intervention protocol. This protocol consisted of intra-umbilical vein injection of misoprostol and if not successful, 250 mu g of sulprostone was given intravenously in 30 min. All vaginal deliveries after 24 weeks of gestation, with RP after 20 min and blood loss <500 mL were included. An intention to treat analysis was performed, with the need for MRP as the primary outcome. Baseline characteristics were similar. In cohort A, 275 women met the inclusion criteria and 57 (20.7 %) women needed MRP. In cohort B, 219 women were included and 35 (16 %) women needed MRP. There was no significant difference in number of MRP, the amount of blood loss and other secondary outcomes. We conclude that the use of intra-umbilical vein injection of misoprostol and intravenous sulprostone consecutively, does not reduce the number of MRPs as well as the total amount of blood loss in women with RP after 20 min. The study shows that changing obstetric management by extrapolating results from specific study groups to a general population may lead to other results.