Case reports and case series have identified putative risk factors for the development of bilateral massive adrenal hemorrhage (BMAH) in humans. The anatomy and physiology of the adrenal gland allow development of a model to fit the pathophysiology behind these risk factors. Until now, these risk factors were not systematically tested using analytical epidemiologic studies. A case-control study was undertaken using sources of cases and controls from multiple teaching hospitals in Ontario, Canada. The results of multivariate logistic regression indicated that thrombocytopenia (odds ratio [OR] = 14.6, 95% confidence intervals [CI] = 3.0-70.1, p < 0.001), heparin exposure of any route or type beyond 3 days (4-6 days: OR = 17.0, CI = 1.9-154.6; > 6 days: OR = 33.5, CI = 4.3-262.6; p < 0.001), and sepsis (OR = 6.3, CI = 1.2-32.2, p = 0.019) were most strongly and independently associated with development of BMAH. Another weaker positive association included invasive radiologic procedure (OR = 4.4, CI = 0.9-22.1, p = 0.055). Neither major surgery or duration of hospitalization were independent risk factors. Although coronary artery disease and possibly diabetes and hypertension appeared to be markers for lower risk of BMAH, this may be a result of bias introduced by using hospital controls ("Berkson bias"), as the effect was not explained by a protective effect of vasoactive medications. Thus, a picture of the high-risk patient should include a patient who has been treated with heparin (any route or type) beyond 3 days and has had thrombocytopenia (not necessarily induced by heparin) during the course of an illness. If the setting includes unexplained abdominal, chest, or back pain; fever; confusion; hypotension or shock; abrupt anemia; or electrolyte disorders, clinicians should not hesitate to cover empirically with lifesaving glucocorticoids while awaiting results of confirmatory tests.