To elucidate the role of the vasodilatory prostacyclin (PGI2) in human ovulation, urinary samples were collected from spontaneously ovulating women (n = 8) and from those undergoing ovulation induction with clomiphene (seven women, 9 cycles) and human gonadotropins (five women, 11 cycles). The samples were assayed for 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a breakdown product of PGI2, employing high-pressure liquid chromatography and radioimmunoassay. The urinary 6-keto-PGF1 alpha was not consistently related to the menstrual cycle day at collection, the occurrence of spontaneous (n = 8) or induced (n = 11) ovulation, or the simultaneous concentration of estradiol in plasma. However, its concentrations both before and after the approximated time of ovulation during clomiphene (41.6 +/- 6.7 and 52.7 +/- 7.9 pmol/mmol creatinine, before/after, mean +/- standard error) or gonadotropin treatment (49.0 +/- 5.8 and 48.1 +/- 6.8 pmol/mmol creatinine) were higher (P less than 0.01) than those in spontaneously ovulating women (26.4 +/- 3.8 and 20.5 +/- 3.0 pmol/mmol creatinine, respectively). Multiple ovarian follicles, as assessed ultrasonographically, developed during four courses of the treatments with gonadotropins, and in three of them the urinary 6-keto-PGF1 alpha was high. The data suggest that treatment with clomiphene and gonadotropin is accompanied by increased production of PGI2, perhaps in the ovaries and/or in the kidneys. This may perhaps play a role in the etiopathogenesis of ovarian hyperstimulation syndrome.