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Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (<jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content>) carotid stenosis to identify pathways linked to plaque instability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Microarrays were prepared from plaques (<jats:italic>n<\/jats:italic> = 127) and peripheral blood samples (<jats:italic>n<\/jats:italic> = 96) of S and <jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content> patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>These studies revealed upregulation of haemoglobin metabolism (<jats:italic>P<\/jats:italic> = 2.20E\u201005) and bone resorption (<jats:italic>P<\/jats:italic> = 9.63E\u201004) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed &gt;1 month compared to &lt;2 weeks after symptom. By prediction profiling, a panel of 30 genes, mostly transcription factors, discriminated between plaques from S versus <jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content> patients with 78% accuracy. By meta\u2010analysis, common gene networks associated with atherosclerosis mapped to hypoxia, chemokines, calcification, actin cytoskeleton and extracellular matrix. A set of dysregulated genes (<jats:italic><jats:styled-content style=\"fixed-case\">LMOD<\/jats:styled-content>1<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">SYNPO<\/jats:styled-content>2<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">PLIN<\/jats:styled-content>2<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">PPBP<\/jats:styled-content><\/jats:italic>) previously not described in atherosclerosis were identified from microarrays and validated by quantitative <jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content> and immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. 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