BACKGROUND Subclinical Cushing's syndrome (SCS) is a well-described phenomenon where abnormalities of the hypothalamic-pituitary-adrenal axis exist in the absence of overt signs and symptoms of classic Cushing's syndrome. While this has been shown to exist in 5-20% of patients with adrenal lesions, no standardized biochemical regimen exists to screen for SCS. Consequently, many of these patients may not be diagnosed prior to adrenalectomy with the risk of postoperative adrenal insufficiency. We began checking morning (a.m.) serum cortisol levels on postoperative day 1 (POD1) following unilateral adrenalectomy for nonfunctioning adrenal lesions to determine the incidence of unrecognized adrenal insufficiency (AI) in these patients. METHODS One hundred and five patients undergoing adrenalectomy at a tertiary care center from 1999 to 2007 were retrospectively evaluated. Patients with Cushing's syndrome, conditions associate with bilateral disease, and those receiving perioperative steroids were excluded, leaving 41 patients for analysis. A.m. serum cortisol levels were obtained in all patients POD1. Multiple factors were analyzed as possible predictors of AI. Analysis of variance (ANOVA), t-test, and chi-square test were used to determine statistical significance. RESULTS The 41 patients' diagnoses included 13 pheochromocytomas, 15 nonsecreting adenomas, 5 aldosteronomas, 5 metastatic lesions, 1 adrenocortical carcinoma, and 2 other benign lesions. Three groups were identified based on POD1, a.m. cortisol levels: sufficient (>10 microg/dl; n = 25, 61%), low-normal (3.4-10 microg/dl; n = 7, 17%), and insufficient (<3.4 microg/dl; n = 9, 22%). Tumor size and presence of diabetes, hypertension, and obesity were predictive of postoperative AI (p < 0.05). CONCLUSIONS AI after unilateral adrenalectomy without evidence of cortisol hypersecretion on preoperative screening was present in a significant number of patients in our series. Patients with diabetes, hypertension, obesity, and larger tumors may be at higher risk for postoperative AI. More thorough screening for cortisol hypersecretion may be warranted in patients with these characteristics, and obtaining routine postoperative cortisol levels may avoid potentially dangerous unrecognized adrenal insufficiency following adrenalectomy.