The omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are prevalent in fish oil and their cardioprotective effects are thought to be mediated by anti-inflammatory mechanisms. The aim of this study is to determine whether omega-3 fatty acids are associated with carotid plaques from neurologically symptomatic patients. Plaques were obtained from 41 patients (mean age 62 [44-84]; 24-asymptomatic, 17-symptomatic). Intra-plaque lipids were assessed with mass spectrometry. Compared to asymptomatic patients, significantly diminished omega-3 fatty acids DHA (545.8+/-98 ng/g vs. 270.7+/-19.6 ng/g, p=0.0096) and EPA (385.9+/-68 ng/g vs. 216.4+/-17.6 ng/g, p=0.0189) were found in carotid plaques from neurologically symptomatic patients. However, no differences were found in the levels of the omega-6 fatty acid arachidonic acid (p=0.2003). Immunohistochemistry and ELISA analysis (CD68(+) cells, 0.461+/-0.04 vs. 0.312+/-0.03, p=0.003) demonstrated an increased inflammatory infiltrate in plaques from neurologically symptomatic, compared to asymptomatic, patients. Carotid plaques from neurologically symptomatic patients are inflammatory and have decreased intra-plaque levels of omega-3 fatty acids. Future trials will determine whether interventions that increase omega-3 fatty acid incorporation into carotid plaques prevent stroke and improve the safety of carotid interventions.