Two progesterone presentations, a vaginal application of 90 mg progesterone per day (Crinone) or 300 mg progesterone orally administered (Utrogestan) were compared for luteal phase support of patients undergoing an in vitro fertilisation (IVF) procedure. 283 patients were randomly allocated to either treatment. The treatment started within 24 hours after the embryo transfer procedure and continued until day 30 in cases of implantation. Efficacy was assessed using the pregnancy and delivery rates. Safety was assessed through specific symptoms and usual safety monitoring. The pregnancy rate per transfer was not significantly different in the Crinone and Utrogestan groups at day 12 (Crinone: 35.3%, Utrogestan: 29.9%, p = 0.55), at day 30 (Crinone: 28.8%, Utrogestan: 25%, p = 0.61), at day 90 (Crinone: 25.9%, Utrogestan: 22.9%, p = 0.69). No difference in spontaneous abortion rates were seen thereafter. The delivery rate was not significantly different (proportion delivery per patients included, Crinone: 23.0%, Utrogestan: 22.2%, p = 1), as well as the ratio new-born per transferred embryo (Crinone: 11.7%; Utrogestan: 11.1%, p = 0.91). Safety parameters were similar in both groups except for drowsiness, which was more significantly frequent in the oral P group than in the Crinone group at all time points. No serious adverse events were recorded in this study. The fact that Crinone matches the efficacy of the larger doses of progesterone used orally reflects an advantage of the transvaginal route of administration which avoids metabolic inactivation of progesterone during its first liver pass.