Objective: To estimate whether administration of 17α- hydroxyprogesterone caproate can prevent neonatal morbidity in multiple pregnancies by reducing the preterm birth rate. Methods: We conducted a multicenter, double-blind, placebo-controlled randomized trial in 55 obstetric clinics in the Netherlands. Women with a multiple pregnancy were randomized to weekly injections of either 250 mg 17α-hydroxyprogesterone caproate or placebo, starting between 16 and 20 weeks of gestation and continuing until 36 weeks of gestation. The main outcome measure was adverse neonatal outcome. Secondary outcome measures were gestational age at delivery and delivery before 28, 32, and 37 weeks of gestation. Results: We randomized 671 women. A composite measure of adverse neonatal outcome was present in 110 children (16%) born to mothers in the 17α-hydroxyprogesterone caproate group, and in 80 children (12%) of mothers in the placebo group (relative risk [RR] 1.34; 95% confidence interval [CI] 0.95-1.89). The mean gestational age at delivery was 35.4 weeks for the 17α-hydroxyprogesterone caproate group and 35.7 weeks for the placebo group (P=.32). Treatment with 17α-hydroxyprogesterone caproate did not reduce the delivery rate before 28 weeks (6% in the 17α- hydroxyprogesterone caproate group compared with 5% in the placebo group, RR 1.04; 95% CI 0.56-1.94), 32 weeks (14% compared with 10%, RR 1.37; 95% CI 0.91-2.05), or 37 weeks of gestation (55% compared with 50%, RR 1.11; 95% CI 0.97-1.28). Conclusion: 17α-hydroxyprogesterone caproate does not prevent neonatal morbidity or preterm birth in multiple pregnancies.