Tehran University of Medical Sciences International Journal of Hematology-Oncology and Stem Cell Research 2008-2207 19 4 2025 10 16 354 364 Alireza Moazedi School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Samaneh Salarvand Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran Zahra Salehi 1)31) Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran 2)Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Alireza Zangooie 1) Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran 2) Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran Leyla Sahebi Maternal-Fetal and Neonatal Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran Alireza Abdollahi Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran Fatemeh Nili Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran Fereshteh Ameli Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran 2025 08 28 2025 10 01 Background: Plasma cell neoplasms (PCNs) are a heterogeneous group of hematologic malignancies that require accurate and timely diagnosis for effective management. Despite the availability of multiple diagnostic tools, challenges remain due to clinical and morphological variability. This study aimed to compare the diagnostic performance of three key modalities, including flow cytometry (FCM), bone marrow aspiration (BMA), and bone marrow biopsy with immunohistochemistry (BMB+IHC) in patients with plasma cell neoplasms. Materials and Methods: A cross-sectional study was conducted on 52 patients with confirmed PCNs. Diagnostic outcomes from FCM, BMA, and BMB+IHC were evaluated and compared. Sensitivity, specificity, predictive values, and inter-method agreement were calculated using SPSS version 27. Results: BMB+IHC achieved the highest diagnostic yield (100%), followed by BMA (55.8%), while FCM demonstrated the lowest diagnostic rate (32.7%). Flow cytometry showed excellent specificity and a positive predictive value of 100%, but limited sensitivity (32.7–58.6%), resulting in a high rate of false negatives. BMA frequently underestimated plasma cell burden due to sampling variability and hemodilution. Collectively, integration of all three methods provided complementary diagnostic value, reducing the risk of misclassification. Conclusion: Bone marrow biopsy with immunohistochemistry remains the gold standard for diagnosing PCNs. However, combining it with aspiration and flow cytometry offers a more comprehensive diagnostic framework, improving accuracy, minimizing false negatives, and supporting optimal patient management.  https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/view/2519 https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/download/2519/1103