A morbidly obese, diabetic, hypertensive patient, with severe intracranial left middle cerebral artery (MCA) stenosis, suffered recurrent stereotyped transient ischemic attacks over 2 months, despite taking daily antiplatelet agents, high dose statin, insulin and an angiotensin converting enzyme inhibitor. A left MCA (M1) Wingspan stent-assisted angioplasty was performed after standard loading, and daily doses of clopidogrel were given 3 days prior to the procedure. Immediately after the procedure, the patient developed a left hemispheric ischemic stroke syndrome. Urgent re-angiography identified an acute intracranial in-stent thrombosis. This complication was immediately treated successfully with abciximab and balloon angioplasty. The patient had persistent residual stroke despite complete recanalization of the thrombosed stent within 3 h of occlusion. The patient was subsequently found to have incomplete inhibition of platelet activity despite being on clopidogrel 150 mg and aspirin 81 mg daily and having a normal CYP-2C19 genotype, suggesting that suboptimal antiplatelet inhibition, secondary to morbid obesity, contributed to his in-stent thrombosis. Obese patients undergoing coronary artery stenting routinely receive larger loading and maintenance doses of clopidogrel. Our case suggests that obese patients undergoing intracranial stenting may also benefit from higher than conventional clopidogrel doses prior to intracranial stenting, to decrease risk of acute in-stent occlusion.