Background Pyrexia of unknown origin (PUO) may be related to several pathologies that need to be identified for proper treatment. PET is found to have highest diagnostic yield in identifying various causes of PUO. The aim of this study is to highlight and justify the use of 18F FDG PET (Fluorine Fluorodeoxyglucose Positron Emission Tomography) imaging as a whole body screening tool in two unique cases of febrile illness with lymphadenopathy but with diverse etiologies based on PET-guided biopsy. The unique arrangement of PET positive nodal disease as a “string of pearls sign” helps in easy identification of nodal disease. Case presentation The first case presented with fever and headache (past history of meningitis), high ferritin level, leukopenia, anemia, and raised inflammatory markers. CSF cell count was high, with mildly elevated protein and low glucose levels. PET positive nodes were biopsied; Kikuchi Fujimoto disease was confirmed with unexpected FDG avid pachymeningeal enhancements on PETMR indicating associated (active) meningitis which would have been missed if CT or MR was done as a standalone imaging. Lumbar puncture confirmed aseptic meningitis. The patient was treated with anti-inflammatory drugs, inj. methylprednisolone, and immunoglobulin together with hydroxychloroquine. The patient improved on follow-up. The second case presented with low-grade fever, pruritis, and nodular swellings in extremities, anemia, and pancytopenia. Based on PETCT findings, biopsy was attempted from FDG avid axillary nodes. Mantle cell lymphoma with rare nodular involvement of cutaneous and subcutaneous tissue was confirmed. Chemotherapy and tyrosine kinase inhibitor therapy was initiated, and the patient is doing well clinically. Conclusion The clinical impact of PET is twofold in both cases. It has accurately identified the nodal involvement even those subcentimetric in size by exhibiting a unique sign on PET resembling a “string of pearls” in the neck and chest with unrelated diverse etiologies. Secondly, additional findings of meningitis in the first case and cutaneous/subcutaneous nodular lymphomatous deposits in the second patient were possible only with whole body FDG PETMR/CT imaging. The rate of additional disease detection by PET is found to be greater than other conventional imaging modalities due to the functional basis of investigation.