The effect of estradiol on interleukin 1 (IL-1) synthesis/secretion by rat peritoneal macrophages was investigated. Peritoneal adherent cells (PAC) from adult female rats secreted greater amounts of IL-1 spontaneously than those from age-matched male rats or prepubescent female rats. Ovariectomy led to reduced synthesis of IL-1 by PAC but estradiol replacement therapy of such rats effectively increased IL-1 synthesis. IL-1 secretion was also stimulated when PAC from male rats was incubated with estradiol. A combination of estradiol and LPS in vitro enhanced secretion of IL-1 by PAC even more than estradiol alone. These data provide new evidence suggesting that estradiol may play an important role in regulating synthesis of IL-1 by macrophages.