Patients with adrenal insufficiency have a life-threatening risk of adrenal crisis, thus preventing adrenal crisis is an important clinical issue. In order to clarify the risk factors for adrenal crisis, the medical records of 137 patients with established adrenal insufficiency were retrospectively investigated. The explanatory variables analyzed were gender, etiology of hypoadrenalism, class of adrenocortical hormone replaced, duration of steroid replacement, age at time of survey, age at time of diagnosis of hypoadrenalism, state of other hormone deficiencies (growth hormone and sex steroids), diabetes insipidus, and mental disorder. Diagnosis of adrenal crisis was based on physical and laboratory findings. Forty (29%) of the 137 patients had at least one episode of adrenal crisis. Based on the Akaike Information Criterion (AIC), steroid replacement therapy of more than 4 yrs' duration was the largest single contributor to the occurrence of an adrenal crisis, followed by mental disorder and sex steroid deficiency. In the subclass of patients with secondary adrenal insufficiency (N = 115), sex steroid deficiency was the greatest risk factor. Patients with untreated hypogonadism had a significantly higher relative risk of 3.70 (95% confidential interval: 1.71-7.98) compared to those without hypogonadism or with treated hypogonadism. Furthermore, among patients with hypogonadism aged younger than 50 yrs, those treated with sex hormone (5/51: 10%) suffered less frequently from adrenal crisis than those untreated (7/11: 64%, p = 0.0004). In conclusion, the present study has, for the first time, clarified the risk factors of adrenal crisis. Among them, sex hormone deficiency has an especially important implication because it can be treated by hormone replacement therapy with the hope of reducing the risk of adrenal crisis.