We aimed to evaluate whether subcapsular injection of ultrasonic contrast agent (UCA) can distinguish between benign and malignant lymph node (LN) lesions exhibiting homogeneous enhancement in intravenous contrast-enhanced ultrasound (CEUS) images. From November 2012 to July 2015, 32 patients with superficial lymphadenopathy exhibiting homogeneous enhancement after intravenous CEUS were enrolled. A small amount of UCA was injected into LNs using a subcapsular approach, and perfusion characteristics were recorded. Using the pathology identified via core needle biopsy as the gold standard, we calculated the sensitivity, specificity and accuracy of the technique in terms of distinguishing between benign and malignant LN lesions. Pathology revealed 23 cases of true benign and 9 cases of true malignant LN lesions; the former included 2 cases of tuberculosis and 21 cases of reactive hyperplasia, and the latter included 7 lymphomas and 2 metastases. Subcapsular CEUS diagnosed 24 benign and 8 malignant LN lesions. Most lymphomas (6 of 7, 85.7%) exhibited heterogeneous perfusion, with lymphatic tract distortion in the absence of interruption. Reactive hyperplasia LNs manifested as diffuse homogeneous or brush-like perfusion from the subcapsular region to the center, without lymphatic tract distortion. Metastatic LNs had lymphatic tract interruptions. The sensitivity, specificity, consistency and positive and negative predictive values were 77.8%, 95.6%, 90.6%, 87.5% and 91.7%, respectively. For LNs exhibiting uniform enhancement in intravenous CEUS imaging, subcapsular CEUS may help to distinguish between benign and malignant lesions. In particular, lymphatic distortion without interruption may specifically indicate a lymphoma. (C) 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved.