Objective: To characterize the response to labor induction with prostaglandin E2 (PGE2) and to identify risk factors for induction failure. Methods: A prospective controlled study of women admitted for labor induction with PGE2. Maternal characteristics, Bishop score and sonographic cervical length were documented at admission. The change in cervical characteristics and the emergence of uterine contractions following each application of PGE2 were analyzed. Results: Of the 88 women who were included in the study, 19 (21.6%) failed to response to PGE2. The following factors were independently associated with induction failure: nulliparity (odds ratio [OR] = 5.9, 95% confidence interval (CI): 1.2–30.2), pre-pregnancy body mass index >25 kg/m2 (OR = 5.4, 95% CI: 1.1–26.5), Bishop score <4 (OR = 2.3, 95% CI: 1.05–14.4), cervical length <25 mm (OR = 0.2, 95% CI: 0.1–0.8) and the development of uterine contractions in response to the first application of PGE2 (OR = 0.4, 95% CI: 0.1–0.93). Overall, most women required only one (60.9%) or two (85.5%) applications of PGE2 to achieve successful induction. The number of applications of PGE2 required to achieve successful induction was related to parity and cervical status at presentation. Conclusions: Overall, most women who eventually respond to PGE2 do so following the first two applications of PGE2, and the contribution of subsequent applications is relatively small and related to cervical status at admission.