Mature male and female mice 50 days of age were challenged with i.v. sodium arachidonate at doses of 12.5, 25, 50 and 100 mg/kg. A dose-dependent response in terms of mortality was observed. Males were significantly more susceptible to arachidonate-induced mortality than females at the 25 and 50 mg/kg doses (P less than .05). The 100 mg/kg dose produced 100% mortality in both sexes. When mice aged 23, 29, 35 and 50 days were challenged with 50 mg/kg of arachidonate, no gender difference was observed until mice were 35 days of age, at which time the male mortality was 80%, compared to 57% for female mice (P less than .05). Mice gonadectomized at 23 days and intact mice 23 days of age were treated with s.c. estradiol, testosterone or vehicle for 7 days before arachidonate challenge. Among these groups, the gonadectomized females and intact males were significantly protected by estradiol when compared to the appropriate controls (P less than .05). In contrast, testosterone pretreatment had no significant effect on mortality. These results demonstrate that the development of the gender difference in arachidonate-induced mortality in mice is dependent upon the presence of gonadal hormones in the immature stages.