Polypoid tongue lesions arising after bone marrow transplantation have been described. Their etiopathogenesis has been unclear, as has their relationship to similar lesions arising in other settings of chronic immunodeficiency. We identified 12 polypoid lesions (from 8 immunosuppressed patients aged 6 months to 13 years) among all tongue lesions biopsied over the course of 13 years at our institution. Clinical history, histologic and ultrastructural features, special stains (Gram, Grocott methenamine silver, acid-fast bacilli, CD34, actin, desmin, human herpesvirus-8), in situ hybridization for Epstein-Barr virus, and cytogenetic features were studied. Immunocompromise was from bone marrow transplantation for severe combined immunodeficiency (n = 1) and acute lymphoblastic leukemia (n = 3), hypogammaglobulinemia (n = 2), 22q11 deletion syndrome (n = 1), and asthma therapy (n = 1). Histologic examination revealed fibrous stromal cores with squamous epithelial covering and various degrees of ulceration and accompanying inflammation and granulation tissue. In 2 patients lesions were multiple in number. Fibroblasts were variably positive for smooth muscle actin and desmin and negative for CD34. Special stains, immunohistochemistry, in situ hybridization, and ultrastructural examination identified no organisms except occasional surface bacteria. The tongue lesion from 1 patient with Down's syndrome showed t(2;9)(p11;q34)+21 (translocation not seen in peripheral blood). Another patient had constitutional del 22q11. All transplant patients had Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) (translocations involving 9q34 and 22q11). Patients with congenital immunosuppression had polyps arise at significantly younger ages than did patients with acquired immunosuppression. Immunosuppression-related lingual polyps are a fibroproliferative process occurring in patients with bone marrow transplantation and other immune-deficient conditions. Our findings indicate that these polyps are driven by both immunosuppression and chromosomal rearrangement.