Pemphigus vulgaris (PV) is an autoimmune blistering skin disease that may require multiagent immunosuppressive drug therapies in severe cases. In addition to the well-established corticosteroid sparing agents azathioprine, mycophenolate mofetil, and methotrexate, rituximab is being increasingly used alone or in combination in the management of PV. Due to the chronic course of the disease, the cumulative effects of these therapy agents over long follow-up periods may result in various adverse reactions, including bacterial and viral infections. Infective endocarditis (IE) is one of the rarest complications of PV treatment with only a few reported cases. In the present study, the present authors discuss two PV patients without prior histories of cardiovascular disease, complicated with native aortic valve IE, which led to death in one of the patients. Because determining the origin of fever is difficult in patients under immunosuppressive therapy, it is particularly challenging to diagnose IE coupled with a fever of unknown origin. Therefore, dermatologists must be vigilant for the dermatological signs of IE and use a multidisciplinary approach to the differential diagnosis of fever of unknown origin.