P-wave widening on the 12-lead electrocardiogram denotes abnormal atrial depolarization and has been shown to be associated with myocardial ischemia during treadmill exercise tolerance testing. However, its true significance during dipyridamole (Persantine) stress imaging remains questionable given the potential direct as well as indirect effects of dipyridamole on the atria. We present a novel series of 5 comparable cases of dipyridamole stress imaging where serial P-wave duration increase occurred during administration of dipyridamole. We observed that such P-wave widening occurred even in the absence of evidence of myocardial ischemia on subsequent myocardial perfusion imaging. Clinicians should therefore be aware of this potential association where, unlike that observed with graded exercise treadmill testing, P-wave widening during dipyridamole infusion could perhaps be a pharmacological effect on the atria instead of an indication of underlying myocardial ischemia.