Dehydrogesterone (DH) induces normal endometrial secretory patterns in infertile as well as post-menopausal women, and has been successfully employed in the treatment of luteal-phase defects. The purpose of this study was to compare DH and progesterone (P) as progestins in steroid replacement cycles in eight women with premature ovarian failure (POF). Patients were treated during two subsequent cycles. Oestradiol valerate was used as the oestrogen. Four women received P as progestin in the first treatment cycle, while the remaining four patients began with DH. Histological dating and total protein content of uterine fluids (PCUF) were used as markers of P action on the endometrium. Samples were obtained on days 18-19 (early luteal phase, ELP) and day 26 of each cycle. Five regularly cycling women served as control for the normal range of PCUF. Histological dating of the endometrium showed ELP out-of-phase glands in 37.5% of cases treated with DH in comparison to none in the P group. Moreover, a characteristic ELP stromal haemorrhagic suffusion and increased oedema were present at the surface of the endometrium in all cases treated with DH. There was no histological difference between treatments on day 26 of the cycle. A significant (P less than 0.05) decrease in PCUF was observed in DH-treated endometria in comparison to P-treated endometria and controls. All three cases dated as out-of-phase endometria in the ELP had a PCUF less than or equal to 0.5 mg/ml. There was no difference between groups in PCUF on day 26. In conclusion, the morphological and biochemical data suggest that the endometrium supplemented with DH in women with POF fails to present optimal conditions for implantation of human embryos in the ELP. It is recommended that oral DH should not replace i.m. P as the progestin in steroid replacement cycles.