OBJECTIVE: To explore the accuracy of unilateral primary aldosteronism (UPA) classification via adrenal vein sampling (AVS) and C-X-C chemoking receptor 4 (CXCR4)-directed positron emission tomography (PET) with METHODS: A retrospective cohort study was conducted with 89 patients who were diagnosed with UPA and who underwent unilateral adrenalectomy (ADX) at West China Hospital of Sichuan University from January 2021 to June 2023. For these patients, surgical decisions were made on the basis of either AVS (AVS group) or CXCR4-directed molecular imaging (CXCR4 group), and patients were regularly followed up for more than 6 months after surgery. Whether biochemical and clinical success was achieved 6 months after surgery was determined on the basis of the primary aldosteronism surgical outcomes (PASO) criterion. The complete success rates were compared between the AVS group and CXCR4 group. One-way analysis of variance was used to compare preoperative factors, postoperative biochemical success rates and clinical success rates between the two groups. Additionally, the postoperative outcomes of adrenal nodules of different sizes were compared. RESULTS: 1. Among the 89 patients with UPA, 66 patients received ADX on the basis of AVS results, and 23 patients on the basis of CXCR4-directed molecular imaging results. The median age of the CXCR4 group [M (P25, P75): 45.00 years (39.00, 51.00)] was significantly lower than that of the AVS group [M (P25, P75): 49.00 years (40.75, 54.00)]. No significant differences in sex, history of hypertension, maximum blood pressure, antihypertensive drug defined daily dose (DDD), plasma aldosterone concentration (PAC), direct renin concentration (DRC), aldosterone-to-renin ratio (ARR), PAC after the captopril challenge test (CCT), PAC after the seated saline infusion test (SSIT), urea nitrogen, estimated glomerular filtration rate (eGFR), serum potassium level, diameter of the adrenal nodules or bilateral adrenal involvement were found. 2. There was no significant difference in the postoperative biochemical complete succcess rate (80.30 vs. 91.30%) or clinical cpmplete success rate (59.05 vs.65.21%) between the AVS group and the CXCR4 group. There were no significant differences in nitrogen, eGFR, serum potassium level, PAC, DRC, ARR, mean postoperative blood pressure or antihypertensive drug DDD after 6 months of follow-up. 3. For the identification of UPA patients with functional adrenal nodules ≥1 cm, CXCR4-directed molecular imaging have comparable diagnostic accuracies. 4. Three patients with adrenal micronodules achieved complete biochemical complete success after successful typing via CXCR4-directed molecular imaging, and unilateral aldosteronogenic micronodules were confirmed by immunohistochemistry (IHC) of CYP11B2 after surgery. CONCLUSION: CXCR4-directed molecular imaging has high diagnostic value in diagnosing UPA. Patients with UPA diagnosed via CXCR4-directed molecular imaging achieved postoperative biochemical and clinical success, with outcomes that appear comparable to those of patients diagnosed on the basis of AVS. CXCR4-directed molecular imaging was more definitive for adrenal nodules larger than 1 cm.