Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) mainly affects young adults and can have a potential impact on social functioning. As this syndrome is associated with endothelial dysfunction, the heart can be damaged via ischemia due to endothelial damage. This might potentially lead to heart failure, which accounts for approximately 20% of deaths among patients with ME/CFS. While cardiac ischemia is thought be a pathophysiologically important manifestation of this syndrome, this is not yet reported. Herein, we present a case of a young female with newly diagnosed vasospastic or microvascular angina and concurrent exacerbation of ME/CFS severity. Her anginal symptoms, including exertional chest pain and transient chest discomfort, mimicked those of ME/CFS but were relieved after the administration of a calcium channel blocker. We emphasize the possibility of concurrent angina and exacerbation of ME/CFS and the importance of detecting cardiac ischemia to avoid unfavorable outcomes.