Background: Following carotid endarterectomy (CEA), cerebrovascular hemodynamic may be hampered by ipsilateral restenosis or development of contralateral stenosis. It remains to be clarified if these patients need follow-up for identifying development of contralateral stenosis. Identification of risk factors contributing to development of contralateral stenosis could allow more specific follow-up. In this current study, we assessed clinical risk factors and plaque characteristics of patients undergoing CEA with development of new contralateral stenosis during mid-term follow-up. Methods: Seven hundred and sixty patients undergoing CEA between 2003 and 2011 at UMC Utrecht were included. Atherosclerotic plaques were excised and analyzed for smooth muscle cells (SMCs), collagen, macrophages, lipid core, plaque hemorrhage and vessel density. Patients underwent clinical and duplex ultrasound follow-up at 3 and 12 months and yearly thereafter. Association between plaque- and patient characteristics with development of contralateral stenosis ≥50% was assessed with univariate and multivariate analysis. Clinical outcome during follow-up was associated with development of new contralateral stenosis. Results: After a median follow-up time of 2.5 years, development of contralateral stenosis was observed in 108 patients (20%). Presence of high collagen (p = 0.025) and high SMC (p = 0.027) was associated with development of new contralateral stenosis, whereas large lipid core was negatively associated with new development of contralateral stenosis (p = 0.034). The same plaque characteristics were related to contralateral occlusion. History of coronary artery disease (p = 0.031) and asymptomatic presentation (p = 0.000) were univariably associated with development of contralateral stenosis. Multiple regression analysis indicated that asymptomatic status was independently associated with contralateral stenosis (p = 0.001). Patients with new development of contralateral stenosis more often showed symptoms during follow-up (p = 0.049). Conclusion: Dissection of a lipid-poor, collagen-rich or SMC-rich plaque yielded an association with development of new contralateral stenosis during mid-term follow-up after CEA. Asymptomatic patients had a significantly higher risk for development of contralateral stenosis. New contralateral stenosis was related to the presence of new cerebral symptoms. These findings may help to develop individual treatment algorithms for patients with cerebrovascular atherosclerotic burden.