Oral thrush is considered as the opportunistic infection, which is caused by fungus Candida albicans. Various kinds of immunodeficiency diseases, such as HIV infection, immunosuppressive therapy, use of broad-spectrum antibiotics, and invasive surgical procedures such as solid organ or bone marrow transplantation, lead to increased susceptibility to fungal infections, but persistent and refractory thrush, with typical clinical signs of oral fungal infection and without any other sign of immunodeficiencies, has not been reported so far. We describe a case of persistent and refractory thrush with Klinefelter syndrome (47, XXY) as the unusual cause.