Abstract Introduction/Objective Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of immune hyperactivation and dysregulation that has been observed in some malignancies. In HLH, natural killer (NK) cells and cytotoxic T-cells fail to control activated macrophages, leading to cytokine-mediated tissue injury and multiorgan failure. Persistent tumor antigenic stimulation and cytokine hypersecretion can trigger HLH. Diffuse large B- cell lymphoma (DLBCL) is uncommonly associated with HLH. Methods/Case Report A 50-year-old woman presented with daily fevers and malaise of one-month duration. Imaging showed marked hepatosplenomegaly with no lymphadenopathy. Laboratory studies were significant for pancytopenia (WBC: 3.8 K/µL, Hb: 6.8 g/dL, Plt: 74 K/µL), hypertriglyceridemia (330 mg/dL), hyperferritinemia (1460 ng/mL), and elevated soluble interleukin-2 receptor (CD25) (42351.5 pg/mL). These findings, along with NK cell activity level (not obtained in this case), fever, splenomegaly and hemophagocytosis (bone marrow, spleen or lymph nodes) represent the eight diagnostic criteria by Histiocyte Society HLH-2004. A splenic biopsy showed a nodular proliferation of medium-to-large neoplastic lymphocytes with CD20, PAX5, BCL6, MUM1, BCL2, CD5 (dim) and CD10 (dim) expression and negative for cyclin D1 and p53. CD21 did not highlight any dendritic cell meshwork. The bone marrow biopsy provided similar results. Overall, these findings were consistent with a DLBCL, germinal center subtype. Rearrangements of MYC, BCL2 or BCL6 genes were not detected. Although hemophagocytosis was not noted in the bone marrow or spleen, the patient met six of the eight HLH-2004 criteria (minimum five are required). The H-score was 174 reflecting up to 70% probability of HLH. Treatment with daily intravenous dexamethasone 10 mg/m2 was initiated as a temporizing measure prior to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy which resulted in complete remission. Results (if a Case Study enter NA) NA Conclusion Physicians should be cognizant of secondary HLH as a rare complication of DLBCL. Prompt initiation of the appropriate therapy could result in rapid and complete resolution.