Abstract Introduction/Objective Malignant effusion is usually caused by metastatic carcinoma. Lymphoma is often not included in the differential diagnoses. Here, we describe two cases of young females with no significant past medical history, presenting with fluid overload. Methods/Case Report The first case is a 41-year-old female with abdominal ascites and pleural effusion. Microscopic examination of the ascitic fluid showed intermediate to large lymphoid cells with irregular nuclear contours and fine chromatin. Flow cytometry showed CD10-positive lambda restricted B-cells. She had retropectoral mass biopsy showing sheets of intermediate to large-sized lymphoma cells with abundant apoptotic bodies and necrosis. The lymphoma cells are positive for CD20, CD10, BCL-2, BCL-6, and C-MYC (~50%,) while negative for TdT and cyclin D1. Proliferative index by Ki-67 stain is ~80%). Fluorescence in situ hybridization (FISH) analysis demonstrated rearrangements of BCL2/18q (80%) and MYC/8q (82%). The patient had a diagnosis of high-grade B-cell lymphoma with MYC and BCL-2 gene rearrangements. The second case is a 43-year-old woman with abdominal pain. She was diagnosed with acute cholecystitis and underwent cholecystectomy. Peritoneal fluid showed numerous neoplastic cells with irregular nuclei, prominent nucleoli, and cytoplasmic vacuoles. Flow cytometry demonstrated CD10-positive B-cells with lambda restriction. The cells were positive for CD10, CD20, BCL-2, BCL-6, and PAX5, and negative for CD34, cyclin D1, HHV-8, and TDT. EBER ISH was negative. The proliferation index by Ki67 stain was >90%. FISH studies showed MYC, BCL2 and BCL6 gene arrangements. Cytogenetic analysis revealed a complex karyotype. A diagnosis of HGBL with triple-hit rearrangements was rendered. Despite receiving aggressive chemotherapy, the patient expired 8.5 months after the diagnosis. Results (if a Case Study enter NA) NA. Conclusion HGBL is an aggressive and often stage IV disease. It should be considered in the differential diagnoses of malignant effusions. Flow cytometry and FISH analysis of the body fluid specimen are essential to reach an accurate diagnosis in a timely manner.