The combined spinal-epidural (CSE) technique for relief of labour pain offers both rapid onset and superior first-stage analgesia. Nevertheless, the known increased risk for early profound fetal bradycardia (EPFB) following CSE continues to be a concern that often limits its use. The purpose of this study was to determine if giving prophylactic intravenous ephedrine at the time of CSE administration would reduce EPFB. We conducted this clinical trial at a large community hospital and enrolled healthy patients requesting epidural analgesia for labour. Patients were randomly assigned to receive either normal saline placebo or ephedrine 10 mg iv at the time of CSE. The primary outcome of EPFB (defined as bradycardia < 90 beats·min(-1) for > two minutes and occurring within the first 30 min after CSE) was compared between groups. The secondary outcomes included the incidence of urgent cesarean delivery, the requirement for additional doses of ephedrine, maternal blood pressure, uterine hypertonus and tachysystole, and abnormal fetal heart rate (FHR) patterns before and after CSE. There were 299 women randomized to the ephedrine (EPH) group and 297 randomized to the normal saline placebo (NS) group. There was no difference between groups in the incidence of EPFB (2.7% EPH group vs 4.7% NS group; relative risk, 0.57; 95% confidence interval, 0.24 to 1.33; P = 0.184). There was also no difference between groups in the incidence of urgent cesarean delivery, uterine hypertonus, uterine tachysystole, and abnormal FHR patterns. We conclude that prophylactic intravenous ephedrine administration at the time of CSE during labour was ineffective at reducing the risk for EPFB associated with CSE. Nevertheless, a lower than expected rate of EPFB resulted in the trial being underpowered. This trial was registered at ClinicalTrials.gov, identifier: NCT02062801.