Preterm delivery is the major determinant of infant mortality and there is a lack of treatments for this condition. Women presenting for prenatal care with a history of a spontaneous preterm delivery were assigned 17 alpha-progesterone caproate (17P) 250 mg/week i.m. between 16 and 20 weeks of gestation or placebo until 36 weeks of gestation or delivery, whichever came first. The primary outcome was preterm delivery before 37 weeks of gestation and this occurred less often in the 17P group than in the placebo group (36.3 versus 54.9%, respectively; p < 0.001). Among the infants, there was a reduction in the risk of a birth weight of < 2500 g in the 17P compared to the placebo group (27.2 versus 41%, respectively). As a result of this clinical trial, 17P should be routinely used as a preventative in women with a history of spontaneous preterm delivery.