We report a case of localized herpes simplex virus lymphadenitis in a patient with mantle cell lymphoma (MCL). A 43-year-old woman with a 2-month history of lymphadenitis and peripheral lymphocytosis received a diagnosis of stage IV MCL based on histologic, flow cytometric, and immunohistochemical findings. One week after completion of chemotherapy, she presented with rapidly enlarging bilateral cervical lymph nodes, a retropharyngeal mass, and incipient respiratory compromise. Multiple biopsies of the cervical nodes and oropharynx that were submitted for morphologic, flow cytometric, and immunohistochemical studies revealed involvement by MCL with superimposed herpes simplex virus lymphadenitis. The recognition of herpes simplex virus infection with MCL is important for treatment as well as to rule out transformation of MCL to a higher-grade lesion.