Most of the clinical features of Cushing’s syndrome (CS) are nonspecific and could be present in obesity, particularly when this condition is associated with metabolic syndrome. Our objective was to evaluate the frequency of clinical manifestations and changes in general laboratory tests, in patients with confirmed endogenous CS, to identify diagnostic dyads. We evaluated in each patient the rate of coexistence of 2 elements either: symptoms, clinical signs, or laboratory alteration. The prevalence of a combined pair of clinical features or dyad in over 30% of the cases, was considered clinically significant. Fourteen dyads were identified as clinically relevant. Facies + buffalo hump; facies + eosinopenia; buffalo hump + supraclavicular fat pads and facies + supraclavicular fat pads, were present in over 50% of cases. Facies + muscular atrophy; centripetal fat distribution + muscular atrophy and facies + striae were present in 42–49%. Hirsutism/acne + eosinopenia; buffalo hump + eosinopenia; muscular atrophy+ eosinopenia; eosinopenia + accelerated weight gain; buffalo hump + muscular atrophy; hirsutism/acne + muscular atrophy and hirsutism/acne + supraclavicular fat pads, were observed in 33–38% of patients. Its application will facilitate the correct diagnosis of CS.