Natural progesterone, which is devoid of androgenic activity, is widely used in assisted reproduction for luteal and pregnancy support. The vaginal route has become the most established way to deliver natural progesterone because it is easily administered, avoids liver first-pass metabolism, and has no systemic side-effects. The vagina has a large potential for absorption, and through the ‘uterine first-pass effect’ vaginal administration results in higher uterine progesterone concentrations. We have investigated the pharmacokinetics of natural progesterone in the form of a vaginal tablet. A single dose of 100 mg resulted in a mean C max of 31.53 ± 9.15 nmol/l with a T max of 6.92 ± 3.12 h. The terminal half-life was 16.39 ± 5.25 h. The pharmacokinetic data are discussed in relation to dose, age, and estrogen priming. Single-dose pharmacokinetics of 100 mg of progesterone vaginal tablets and gelatin capsules were evaluated over 24 h. Results indicated a similar mean T max of 6.92 ± 3.12 and 6.23 ± 6.57 h, respectively. However, a significantly higher C max was achieved by the vaginal tablet (31.95 ± 9.15 and 23.85 ± 9.57 nmol/l, respectively, P < 0.05). Continuous use of vaginal progesterone did not influence the hormonal, liver, or lipid profiles evaluated. There was no case of endometrial hyperplasia. The vaginal tablet was found to be well-tolerated, safe, and easily administered. In conclusion, progesterone-containing vaginal tablets have good pharmacokinetic properties and should be used for progesterone supplementation in IVF.