Sexual dimorphism in critical diseases has been documented. Severe acute pancreatitis is a disease with high mortality. We hypothesized that admission sex hormone levels may be used as an early predictor of outcome in these patients. A prospective cohort of patients with severe acute pancreatitis admitted to the intensive care unit for at least 48 h were enrolled (n = 62). Serum levels of estradiol, progesterone, and testosterone were determined on admission. The association of sex hormone levels and various disease severity scoring systems with patient outcome was analyzed. There was no difference in overall mortality between the sexes. However, estradiol was significantly elevated in nonsurvivors (39 vs. 206 pg/mL, p < 0.001). The estradiol level was the best single-variable predictor of mortality (area under the curve 0.97), followed by the sequential organ failure assessment score, the multiple organ dysfunction score, and the acute physiology and chronic health care evaluation II (APACHE II) score. A serum estradiol level of 102 pg/mL was both sensitive and specific to predict mortality. There were no differences between survivors and non-survivors in terms of age, body mass index, or progesterone and testosterone levels. Admission serum estradiol level is a good marker of disease severity and predictor of death in patients with severe acute pancreatitis.