Background: EUS-guided FNA of the left and right adrenals has been described, but data are very limited. Objectives: Our primary objective was to determine the impact of the diagnostic utility of EUS-guided FNA of adrenal glands on patient management. Our secondary objective was to determine predictors of malignant adrenal involvement. Study Design: Observational study. Setting: Tertiary referral center. Patients: Patients with enlarged adrenal(s) on abdominal imaging underwent EUS-guided FNA. The left adrenal (n = 54) was sampled via the transgastric approach and the right adrenal (n = 5) via a transduodenal approach. Results: Fifty-nine patients (63% men, median age 65 years) were evaluated. The median adrenal gland size was 25 × 17 mm. Adrenal tissue adequate for interpretation was obtained in all of the patients. EUS-guided FNA confirmed malignancy in 22 (37%) patients. Based on size (≥30 mm) alone, EUS had an accuracy of 68%. Patients with malignant cytology had higher standard uptake value scores on positron-emission tomography compared with patients with benign adrenal masses (P < .001). Malignant masses were more likely to have an altered adrenal gland shape compared with benign masses (crude odds ratio [OR] 12.0; P < .001). On multivariable analysis, altered adrenal gland shape was a significant predictor of malignancy (adjusted OR 7.94; P = .015), whereas a size of 30 mm or larger (adjusted OR 1.30; P = .774) and hypoechoic nature (adjusted OR 12.05; P = .148) were not. All patients except 2 with malignant cytology were treated with systemic therapy without the need for additional invasive biopsies or surgery. No immediate complications were encountered. Limitations: Lack of surgical criterion standard; 1 experienced endosonographer. Conclusions: EUS-guided FNA of the adrenal glands is a minimally invasive and safe approach that documents or excludes malignant involvement. EUS-guided FNA should be the first next test to evaluate enlarged adrenal glands because it directs therapy and affects patient management. © 2010 American Society for Gastrointestinal Endoscopy.