A 55-year-old female was referred to the medical hematology service for severe anemia and osteolytic lesions in the spine and skull. At the time of consultation, the hemogram showed "lymphocytosis," with the automated analyzer misidentifying plasma cells as lymphocytes, and the peripheral blood smear revealed cells resembling hairy cells, raising suspicion of hairy cell leukemia or plasma cell leukemia. The patient was requested to undergo a series of laboratory tests to perform a differential diagnosis between the two conditions. Laboratory findings were as follows: Hemoglobin: 6.7 g/dL (normocytic-normochromic anemia); Leukocytes: 48,620 cells/μL (leukocytosis); Platelets: 128,000 cells/μL (thrombocytopenia); Creatinine: 2.6 mg/dL; Calcium: 14.2 mg/dL (hypercalcemia); Beta-2-microglobulin: 42 mg/L; LDH: 146 U/L; Total proteins: 7 g/dL; Albumin: 4 g/dL. Peripheral blood morphology confirmed anemia and thrombocytopenia with 72% plasmacytoid cells. Serum protein electrophoresis revealed a monoclonal band in the mid-gamma region (1.5 g/dL). Immunofixation identified a monoclonal component of free Lambda light chains. Immunoglobulin levels were markedly reduced (IgG: 375 mg/dL, IgA: 10 mg/dL, IgM: 4 mg/dL), and no monoclonal bands were detected in urine. Peripheral blood was examined by multiparametric flow cytometry using first an LST tube and then plasma cell panel with the CytoFLEX BC cytometer. Using CD138/CD38 gating strategy identified 75% circulating leukocytes as plasma cells with a neoplastic phenotype. These cells expressed CD38 and CD138 but lacked CD19, CD45, CD56, CD117, and CD27, with cytoplasmic lambda light chain restriction. Bone marrow examination was deferred at the time of diagnosis. FISH analysis for IGH/FGFR3 t(4;14), IGH/MAF t(14;16), and p53 gene deletions (17p13.1) showed no abnormalities. Based on international criteria for plasma cell leukemia (PCL)—defined as ≥ 20% and ≥ 2000/μL plasma cells in peripheral blood—the diagnosis of primary PCL was confirmed. The patient’s clinical presentation, including hypercalcemia, anemia, and osteolytic lesions, supported the diagnosis. Discussion: PCL is a rare and aggressive form of multiple myeloma characterized by circulating plasma cells. Morphological variability of plasma cells can complicate diagnosis; cells may mimic lymphocytes, monocytes, or hairy cells. Key diagnostic tools include bone marrow studies, flow cytometry, and a comprehensive myeloma profile, including serum protein electrophoresis, immunofixation, free light chain assay, and 24-hour urine analysis. Management and Conclusion: Given the poor prognosis and aggressive nature of PCL, treatment was initiated promptly with a bortezomib-based regimen. PCL highlights the importance of accurate diagnostic methods to guide timely and appropriate therapy.