DNA repair disorders predispose the development of primary immunodeficiency and lymphoma. Epstein-Barr virus (EBV)-associated B-cell lymphomas and precursor T-cell lymphoblastic leukemia/lymphomas are described in ligase 4–deficient (LIG4) patients, presenting with variable T- and B-cell immunodeficiency, radiosensitivity, microcephaly, developmental delay, and cytopenias.1 We report on one of the first patients, 411BR, who carried a homozygous 833G>A/R278H mutation and 2 cooperating homozygous N-terminal single nucleotide polymorphisms.2 Despite remaining well for many years, albeit with profound learning difficulties, persistent anemia, thrombocytopenia and lymphopenia, bronchiectasis, and combined immunodeficiency treated with immunoglobulin replacement (see Table E1 in this article's Online Repository at www.jacionline.org), he re-presented at 23 years of age with rapidly enlarging cervical lymphadenopathy. EBV was negative in blood by PCR. Biopsy revealed diffuse large B-cell lymphoma (DLBCL). Computerized tomography with contrast showed bilateral nasopharyngeal masses with extensive cervical lymphadenopathy (Ann Arbor stage IIA disease). Because of radiosensitivity and cytopenias, dexamethasone, rituximab, and low-dose cyclophosphamide were given, with 1 dose of lomustine, an alkylating nitrosourea compound. The absence of a suitable donor precluded allogeneic hematopoietic stem cell transplantation and the patient died.