Referred pain is frequently associated with misdiagnosis and unnecessary therapy directed to the pain location instead of its origin. When craniofacial pain is the sole symptom of myocardial ischemia, failure to recognize its cardiac source can endanger the patient. In particular, patients with acute myocardial infarction (AMI) who do not experience chest pain run a very high risk of misdiagnosis and death. Pain that is limited to the craniofacial region during myocardial ischemia has so far been described only in case reports and its overall prevalence is unknown. Experimental research in animals suggests a vagal involvement in the pathological mechanisms of cardiac pain referred to the face. The aim of this study was to gain knowledge about the prevalence, clinical characteristics and possible mechanisms of craniofacial pain of cardiac origin, in order to improve the clinician’s ability to make a correct diagnosis. It was hypothesized that the quality of craniofacial pain from cardiac versus dental origin would differ, implying a high diagnostic validity. It was also hypothesized that craniofacial pain can be the sole symptom of a prodromal (pre-infarction) angina episode and that this pain location would be especially associated with cardiac ischemia in the areas more densely innervated by vagal afferent fibres. The study group was comprised of consecutive patients who experienced craniofacial pain of a verified cardiac (n=326) or dental (n=359) origin. Demographic details on age, gender and pain characteristics (location, quality and intensity) were assessed in both groups. Cardiovascular risk factors, cardiac diagnosis and ECG signs of ischemia were also assessed in the cardiac pain group. Ethics approval and informed consent for each patient was obtained. Craniofacial pain was found to be the sole symptom of myocardial ischemia in 6% of patients and was the sole symptom of an AMI in 4% of patients; this craniofacial pain was more prevalent in women (p=0.031). In those patients without chest pain, it was the most frequent pain location and was the only symptom of prodromal angina in 5% of AMI patients. The craniofacial pain included the throat, the jaws, the temporomandibular joints/ears and the teeth, mainly bilaterally. The pain quality descriptors “pressure” and “burning” were statistically associated with pain of cardiac origin, while “throbbing” and “aching” were associated with an odontogenic cause (p<0.001). In myocardial ischemia patients, the occurrence of craniofacial pain was associated with an inferior localization of ischemia in the heart (p<0.001). In conclusion, this study showed that pain in the craniofacial region could be the sole symptom of cardiac ischemia and AMI, particularly in women. Craniofacial pain of cardiac origin was commonly bilateral, with the quality pain descriptors “pressure” and “burning”, and pain provocation with physical activity and pain relief at rest. The association between the presence of craniofacial pain and inferior wall ischemia suggests a vagal involvement in the mechanisms of cardiac pain referred to the craniofacial region. Since the possibility of misdiagnosis and death in this group of patients is high, awareness of this clinical presentation needs to be brought to the attention of researchers, clinicians and the general public.