A 30-year-old, HIV-positive man with a previous history of an atypical nasopharyngeal Burkitt lymphoma developed fluorodeoxyglucose (FDG) avidity on a routine FDG-positron emission tomography (PET)/computed tomography scan performed 10 months after the completion of all treatment. This new FDG-avid disease was in the area of his initial disease. Flow cytometric assessment of a fine needle aspiration showed a CD10-expressing B-cell population with kappa predominance. The corresponding cytology smears had large atypical lymphoid cells along with smaller lymphocytes and macrophages. Because of the patient's previous history of a CD10(+), high-grade B-cell lymphoma, the cytologic and flow cytometric findings were considered highly suspicious for a B-cell lymphoma. Because the differential diagnosis included a relapsed Burkitt lymphoma versus a second, unrelated lymphoma (the former with a dismal prognosis) it was deemed prudent to obtain more tissue via an open biopsy for confirmation of diagnosis and exact subclassification. An open biopsy, however, revealed a reactive lymph node with enlarged geographic follicles; no lymphoma was demonstrable and c-Myc studies were negative. The patient remains without evidence of disease. Retrospectively, the original flow cytometric assessment was believed to likely represent sampling of hyperplastic germinal centers with significantly expanded CD10(+) B cells. The FDG uptake and the kappa predominance further confounded the interpretation. This case illustrates the pitfalls of standard diagnostic techniques, including PET scanning, cytology, and flow cytometry, particularly in the setting of HIV. It further underscores the importance of adequate clinical correlation and a low threshold for performing open biopsies in such patients.