BACKGROUND: We investigated the possibility of correcting the endometrial alterations induced with clomiphene citrate (CC) by vaginal hormonal supplementation (HS) with estradiol (E2) and progesterone gel. METHODS: Oligo-ovulatory women were prospectively randomized into four groups receiving either 50 mg (groups 1 and 2) or 100 mg (groups 3 and 4) of CC from cycle day 3-8. Groups 2 and 4 also received vaginal E2 cream 0.1 mg twice daily from day 8 until the LH surge and vaginal progesterone gel, starting 3 days after ovulation. All participants had an endometrial biopsy performed 10 +/- 1 days after ovulation. RESULTS: All biopsies in the HS groups (2 and 4) showed complete predecidual changes, and were 'in-phase' with findings normally made 10 days post-ovulation (+/- 2 days of clinical dating). However, without HS (groups 1 and 3), only 4/6 and 3/6 biopsies showed predecidual changes in women receiving 50 and 100 mg of CC. CONCLUSION: The addition of vaginal E2 and progesterone to CC ovulation induction regimens normalizes the alterations in endometrial morphology. Hormonal treatment combining vaginal E2 and progesterone may improve endometrial receptivity in CC cycles and ultimately yield higher pregnancy rates.