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The diagnosis of Cushing's syndrome requires highly sensitive screening tests. Therefore, diagnostic cutoffs have been lowered to maximize sensitivity and identify all patients. However, few studies have investigated the impact of these refinements on the specificity of first-line tests.The aim of the study was the assessment of the specificity of three widely used screening tests in a large series of Cushing's syndrome suspects referred to our endocrine service.We retrospectively reviewed the results of urinary free cortisol (UFC), 1-mg dexamethasone suppression test [overnight suppression test (OST)], and serum cortisol at midnight in 3,461, 357, and 864 patients, respectively, with clinical features suggestive of Cushing's syndrome but in whom this diagnosis was subsequently excluded.UFC and OST at the 5-microg/dl cutoff exhibited the highest specificities [91% (95% confidence intervals [CI] 90.2-92.1%) and 97% (95% CI 96.3-98.5%), respectively]. Conversely, midnight serum cortisol yielded 87% (95% CI 84.3-91.1%) specificity only with the 7.5-microg/dl cutoff, whereas the 1.8-microg/dl threshold resulted in an unacceptably high proportion of false positives at only 20% specificity (95% CI 16.0-24.4%). Gender and age may lead to misleading results in all three screening tests.Specificity of tests for Cushing's syndrome varies considerably, with OST and UFC presenting the best performances, and circadian rhythm appearing heavily impaired by lowering of diagnostic cutoffs. Indeed, the vast majority of individuals in our series presented midnight serum cortisol values greater than 1.8 microg/dl; thus, caution has to be exercised when this criterion is used to exclude Cushing's syndrome.