SPECT and PET myocardial perfusion imaging (MPI) are widely used to evaluate patients for coronary artery disease. Regadenoson (a selective A adenosine receptor agonist) is a commonly used vasodilator agent for stress MPI because of its safety profile and ease of use. Common adverse reactions such as headache, shortness of breath, flushing, and chest and abdominal discomfort are typically mild and can be effectively reversed using methylxanthines such as aminophylline and caffeine. Neurological adverse reactions such as seizure and stroke have rarely been reported with the use of regadenoson. The hemodynamic changes associated with regadenoson administration, such as an exaggerated hypotensive or hypertensive response, may be the cause for the reported cerebrovascular accidents. Activation of central nervous system A adenosine receptors is thought to be responsible for seizure episodes in patients with or without known histories of seizure. A adenosine receptors activation is also believed to play a role in headaches and migraine. This patient reported who has a history of hemiplegic migraine developed left side weakness and headache following the administration of regadenoson during a PET MPI study. Imaging work-up to rule out cerebrovascular accident was normal. After 1 hour from the onset of his symptoms, his weakness and headache significantly improved with complete resolution within 24 hours. We concluded that regadenoson triggered a hemiplegic migraine episode in this patient, which has not been previously reported in the literature. It may be prudent to avoid regadenoson and adenosine use in patients with a history of hemiplegic migraine.