OBJECTIVE: To compare the efficacy, side effects, and complications of high-dose vaginal misoprostol with concentrated intravenous oxytocin plus low-dose vaginal prostaglandin (PGE2) for second-trimester labor induction. METHODS: One hundred twenty-six consenting women with maternal or fetal indications for pregnancy termination and no prior cesarean delivery were randomly assigned to receive either vaginal misoprostol 600 μg 1 ×, 400 μg every 4 hours 5× (misoprostol group, n = 60) or escalating-dose concentrated oxytocin infusions (277-1,667 mU/min) plus vaginal PGE2 10 mg every 6 hours 4× (oxytocin group, n = 66). Both groups received concurrent extra-amniotic saline infusion for cervical ripening. Women who failed their assigned regimen received 20 mg of PGE2 suppositories every 4 hours until delivery. Analysis was by intent to treat. RESULTS: Demographic characteristics were similar between study groups. Median induction-to-delivery interval was significantly shorter in the misoprostol group (12 hours) than in the oxytocin group (17 hours; P < .001). There was a higher induction success rate at 24 hours in the misoprostol group (95%) than in the oxytocin group (85%; P = .06), although this difference did not reach statistical significance. The incidence of live birth (25% versus 17%), chorioamnionitis (5% versus 2%), and postpartum hemorrhage greater than 500 mL (3% versus 3%) were similar between the misoprostol and oxytocin groups, respectively. Diarrhea (2% versus 11%; P = .04), nausea/emesis (25% versus 42%; P = .04), and retained placenta requiring curettage (2% versus 15%; P = .008) were significantly less common in the misoprostol group when compared with the oxytocin group, respectively. Isolated intrapartum fever, however, was more frequent in the misoprostol group (67%) than in the oxytocin group (21%; P < .001). CONCLUSION: Compared with concentrated oxytocin plus low-dose vaginal PGE2, high-dose vaginal misoprostol is associated with significantly shorter induction-to-delivery intervals, fewer side effects, a lower incidence of retained placenta, and comparable incidence of live birth. © 2004 by The American College of Obstetricians and Gynecologists.