INTRODUCTION: Primary aldosteronism affects 20% of patients with resistant hypertension and may be due to unilateral or bilateral causes. Patients with a unilateral source of aldosterone secretion are potentially curable with adrenalectomy. Adrenal vein sampling (AVS) is the definitive test for subtype differentiation but may not be accessible outside tertiary centers. The goal of this study was to determine whether clinical characteristics can predict a unilateral source of aldosterone on AVS. METHODS: Patients with a biochemical diagnosis of primary aldosteronism who underwent AVS between 1998 and 2019 were identified from a prospectively maintained database. Unilateral aldosterone secretion was defined as lateralization index ≥4. Univariate and multivariate logistic regression were used to assess the correlation between clinical characteristics and unilateral aldosterone secretion. A risk score was developed to predict a unilateral source of aldosterone. RESULTS: Of 461 patients, 61% were male and 39% female. The mean age was 54 ± 11 y, and median duration of hypertension was 10 (interquartile range: 5-20) y. A total of 324 patients had unilateral aldosterone secretion. On multivariate logistic regression analysis, non-Black race, lower body mass index, shorter duration of hypertension, and nonincidental diagnoses were significantly associated with a unilateral source of aldosterone. Neither age nor an adrenal adenoma on imaging was predictive of a unilateral aldosterone source. The clinical risk score had an 86% positive predictive value for a unilateral source of aldosterone. CONCLUSIONS: Clinical characteristics imperfectly predict subtype differentiation. However, high clinical risk scores have a strong positive predictive value for a unilateral source of aldosterone.