Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immune defect, and predisposition to leukemia/lymphoma. Because of their hypersensitivity to DNA-damaging agents, patients with A-T may require special consideration. However, an optimal strategy for these patients has not been established. Here, we describe an A-T female with diffuse large B-cell lymphoma successfully treated with rituximab combined with reduced-dose chemotherapy. Given the high incidence of hematopoietic malignancies in patients with A-T, and the hypersensitivity of these patients to DNA-damaging agents, we discuss whether a reduced-dose chemotherapy with a molecular targeting agent may be of merit.