Purpose: To evaluate the empirical use of progesterone (P) in the luteal phase for unexplained infertility. Methods: Clinical and livedelivered pregnancy rates in three treatment cycles were compared in women with unexplained infertility vs women taking follicle maturing drugs for women completely anovulatory or those who release the oocyte before the follicle is mature. Results: There was insufficient power to show a significant difference in the 19.5% live-delivered pregnancy rate found in women with a mean length of infertility duration of 2.1 years who just used P in the luteal phase vs the 30.1% rate seen in women with clear-cut ovulatory defects treated with follicle-maturing drugs in the follicular phase and P in the luteal phase. Conclusions: Though a larger study would possibly show a lower pregnancy rate in those women with unexplained infertility empirically treated with P vs the women with ovulation defects, the empirical use of P allows easy treatment without the side-effects of follicle-maturing drugs, e.g., hostile cervical mucus, vasomotor symptoms or ovarian cysts. The study was not designed to determine if empirical use of follicle-maturing drugs with P support for unexplained infertility would be more effective than P supplementation alone.