OBJECTIVE: Carotid endarterectomy for symptomatic carotid stenosis is recommended for patients with >70% stenosis, but not in those with <50%. Because non-significant, low-degree stenoses may still cause strokes, refined risk stratification is necessary, which could be improved by assessing biological features of plaque instability. To challenge risk-stratification based on luminal narrowing, we compared biological features of carotid plaques from symptomatic patients with low-degree (<50%) vs high-degree (>70%) stenosis and explored potential mechanisms behind plaque instability in low-degree stenoses. METHODS: Endarterectomy specimens were taken from symptomatic patients with high-degree (n = 204) and low-degree (n = 34) stenosis, all part of the Biobank of Karolinska Endarterectomies. Patient demographics, image-derived plaque morphology, and gene expression analyses of extracted lesions were used for comparisons. Plaque biology was assessed by transcriptomics using dimensionality reduction, differential gene expression, and gene-set enrichment analyses. Immunohistochemistry was used to study proteins corresponding to upregulated genes. RESULTS: The demographics of the two groups were statistically similar. Calcification, lipid-rich necrotic core, intraplaque hemorrhage, plaque burden, and fibrous cap thickness were similar in both groups, whereas the sum of lipid-rich necrotic core and intraplaque hemorrhage was higher ( = .033) in the high-degree stenosis group. Dimensionality reduction analysis indicated poor clustering separation of plaque gene expression in low-compared with high-degree stenosis lesions, whereas differential gene expression showed upregulation of hypoxia-inducible factor 3A (log fold change, 0.7212;  = .0003), and gene-set enrichment analyses identified pathways related to tissue hypoxia and angiogenesis in low-degree stenoses. Hypoxia-inducible factor 3-alpha protein was associated with smooth muscle cells in neo-vascularized plaque regions. CONCLUSIONS: Plaques from symptomatic patients with non-significant low-degree carotid stenoses showed morphologic and biological features of atherosclerotic plaque instability that were comparable to plaques from patients with high-degree stenoses, emphasizing the need for improved stroke risk stratification for intervention in all patients with symptomatic carotid stenosis irrespective of luminal narrowing. An increased expression of hypoxia-inducible factor 3A in low-degree stenotic lesions suggested mechanisms of plaque instability associated with tissue hypoxia and plaque angiogenesis, but the exact role of hypoxia-inducible factor 3A in this process remains to be determined. CLINICAL RELEVANCE: Carotid plaques from symptomatic patients with <50% stenosis show morphologic and biological features of plaque instability, comparable to high-degree stenosis, which emphasizes the need for improved stroke risk stratification beyond stenosis severity.