OBJECTIVE: Progesterone has a known diabetogenic effect. We sought to determine whether the incidence of gestational diabetes mellitus (GDM) is altered in women receiving weekly 17alpha-hydroxyprogesterone caproate (17P) prophylaxis for the prevention of recurrent preterm birth. RESEARCH DESIGN AND METHODS: Singleton gestations in women having a history of preterm delivery were identified from a database containing prospectively collected information from women receiving outpatient nursing services related to a high-risk pregnancy. Included were patients enrolled for outpatient management at <27 weeks' gestation with documented pregnancy outcome and delivery at >28 weeks. Patients with preexisting diabetes were excluded. The incidence of GDM was compared between patients who received prophylactic intramuscular 17P (250-mg weekly injection initiated between 16.0 and 20.9 weeks' gestation) and those who did not. RESULTS: Maternal BMI and age were similar. The incidence of GDM was 12.9% in the 17P group (n = 557) compared with 4.9% in control subjects (n = 1,524, P < 0.001; odds ratio 2.9 [95% CI 2.1-4.1]). CONCLUSIONS: The use of 17P for the prevention of recurrent preterm delivery is associated with an increased risk of developing GDM. Early GDM screening is appropriate for women receiving 17P prophylaxis.