Background: The rate of multiple pregnancies in IVF/ICSI ranges from 20-30% . The incidence of preterm birth in multiple pregnancies is as high as 60% and is even higher in pregnancies conceived after IVF & ICSI. The effect of progesterone on prevention of preterm birth in twins is controversial . Our group has proven a positive effect in reduction of preterm birth ,by starting progesterone from the mid-trimester ,in exclusively IVF/ICSI singleton pregnancies but not twins. The purpose of our current study was to explore the effect of earlier administration of natural progesterone, in IVF/ICSI twin pregnancies starting at 11-14 weeks for prevention of preterm birth. Methods: This is a double-blind, placebo controlled, single center, randomized clinical trial. Women with dichorionic twin gestations, following an IVF/ICSI trial were randomized to receive natural rectal progesterone (800 mg daily ) vs placebo, starting early from 11-14 weeks. They were randomized regardless of cervical length and had no previous history of preterm birth or known Mullerian anomalies. The primary outcome was, spontaneous preterm birth rate <37 weeks. The secondary Outcome was; spontaneous preterm birth <34,32,28 weeks and neonatal outcome. Results: A total of 203 women were randomized to both groups, final analysis included 199 women as 4 were lost to follow up. The base line characteristics as well as gestational age at delivery were not significantly different between the study and the placebo group (34.7±3.6 vs 34.5±4.5, P=0.626). Progesterone administration was not associated with a significant decrease in the spontaneous preterm birth rates <37 weeks (73.5% vs 68%, P = 0.551), <34 (20.6% vs 21.6%, P = 0.649), <32 (8.8% vs 12.4%, P = 0.46) & <28 (4.9 % vs 3.1 %, P = 0.555). Conclusions: Rectal natural progesterone starting from the first trimester in IVF/ICSI twin pregnancies did not reduce spontaneous preterm birth.The trial was registered on 31 January 2014 at www.ISRCTN.com, 69810120.