BackgroundAmerican College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) being most widely applied in clinical practice, there is an overlap in US imaging manifestations between benign and malignant thyroid nodules. ObjectivesTo analyze the imaging and histological characteristics of pathological benign thyroid nodules categorized as American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) 4 or 5, and to explore the correlation between the suspicious sonographic signs resulting in the misdiagnoses and the histopathological features. Materials and methodsOverall, 227 benign thyroid nodules (215 patients) in ACR TI-RADS 4 or 5 sampled through surgical excision were analyzed between December 2020 and August 2022. We retrospectively reread the ultrasound (US) images of the pathological discordant cases, after which we performed a systematic analysis focusing on the histopathological characteristics of thyroid lesions and recorded the findings. Qualitative US features and pathological significance of the thyroid nodules were analyzed using the chi-square and Fisher’s exact tests. ResultsThe pathological type of 227 thyroid nodules (n = 103 in ACR TI-RADS 4 and n = 124 in ACR TI-RADS 5) was nodular goiter together with other histopathological features, namely, fibrosis (n = 103, 45.4 %), calcification (n = 70, 30.8 %), adenomatous hyperplasia (n = 31, 13.7 %), follicular epithelial hyperplasia (n = 23, 10.1 %), Hashimoto’s thyroiditis (n = 18, 7.9 %), and cystic degeneration (n = 16, 7.1 %). Fibrosis was the most common histopathological feature in both ACR TI-RADS 4 (n = 42, 40.8 %) and 5 (n = 61, 49.2 %) categories of benign thyroid nodules. Thyroid nodules with fibrosis demonstrated sonographic features of “taller than wide” (p < 0.05), while lesions with follicular epithelial hyperplasia were likely to be detected with irregular and/or lobulated margins and very hypoechoic on US (p < 0.05 for both). ConclusionBenign thyroid nodules with histopathological findings such as fibrosis are associated with suspicious US features, which may give inappropriately higher TIRADS stratification.