One hundred forty four fertile women were treated cyclically with a daily dose of 5 mg of 6-methyl-6-dehydro-17a-acetoxyprogesterone (megestrol acetate) + 0.1 mg of 17a-ethynyl-oestradiol-3-methylether (mestranol) for a period of 1 to 24 months. The excretion of pregnanediol on days 21 to 23 never exceeded 0.9 mg/ day, and there was no correlation between the excretion of pregnanediol and the length of the treatment period. In 62 fertile women it was shown by laparotomy, that inhibition of ovulation was extremely reliable when treatment with megestrol acetate + mestranol was iniated at the latest day 7. If the treatment was started later than day 7 then the inhibition of ovulation was increasingly unreliable, and from day 10 there was no inhibition of ovulationo As could be expected the excretion of pregnanediol on day 23 was invariably low in all patients who did not show any sign of recent ovulation. More surprising was the finding of a low excretion of pregnanediol in 6 patients in whom fresh corpora lutea were found at laparotomy on day 24. This finding might be due either to an impaired function of the corpus luteum or to an influence of the steroids on the metabolism of progesterone or on the analysis used for the determination of pregnanediol. Sixteen fertile women underwent laparotomy on days 24 to 26, and in the cycle in which the laparotomy was performed, treatment was initiated on day 10 or later with megestrol acetate only, mestranol only, or the combination of both substances. All patients showed fresh corpora lutea. Not only megestrol acetate + mestranol, but also megestrol acetate only suppressed the excretion of pregnanediol in the late part of the cycle when treatment was initiated before ovulation, whereas mestranol only caused no decrease in the pregnanediol excretion. If treatment with megestrol acetate + mestranol was started after ovulation then the excretion of pregnanediol was not suppressed, but the luteal phase was shorter than usual. In addition, it was observed in 3 postmeno-pausal women, that megestrol acetate caused no significant changes in the excretion of pregnanediol following intramuscular administration of progesterone. It is therefore concluded that the low excretion of pregnanediol observed during treatment with megestrol acetate + mestranol in patients showing fresh corpora lutea, is due to an impaired function of the corpus luteum and not to a change in the metabolism of progesterone. It appears that megestrol acetate is responsible for this effect.