We describe two women who suffer from recurrent fever up to 40 C in association with progesterone action and who have continuously elevated serum levels of immunoreactive tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6). In patient 1, recurrent fever began at age 17 yr and has now continued for 11 yr. The patient has had three early pregnancy terminations because of continuous fever and, thereafter, three early pregnancy losses associated with fever. In patient 2, fever first appeared at age 18 yr, and the attacks have now continued for 3 yr. The association between fever and progesterone action is supported by the following facts. 1) The episodes of fever appear in the midluteal phase of the menstrual cycle concomitantly with the highest concentration of serum progesterone. 2) Fever is further exaggerated in early pregnancy. 3) Synthetic progestins induce fever regardless of the day of the menstrual cycle. 4) The progesterone antagonist RU 486 and an agonist of GnRH, nafarelin, are capable of preventing the fever, with no effect on serum cytokine levels. Although the underlying mechanism of elevated TNF alpha and IL-6 levels in our patients remains unknown, the data suggest that these cytokines cooperate with progesterone in exerting a pyrogenic response in the hypothalamic thermoregulatory center.