Abstract Introduction/Objective Diffuse large B-cell lymphomas, the most common Non-Hodgkin’s lymphoma are heterogeneous in terms of varied clinical presentation. The pathological work up these lymphomas is usually initiated with a CD20/CD3 immunohistochemical panel. Due to the aggressive nature of these lymphomas, pre-diagnosis corticosteroids are necessitated in some cases. However, the corticosteroids treatment can significantly alter the antigen staining of the lymphoma delaying the pathological diagnosis and subsequent treatment. This study investigates how pre-biopsy corticosteroids administration affects CD20 staining in B-cell lymphoma cells along with CD3 and PAX5, aiming to provide insights to the practicing pathologist for prompter diagnosis in these challenging cases. Methods/Case Report 14 biopsy cases of B-cell lymphoma pretreated with corticosteroids were included in this study. Clinicopathological parameters including corticosteroids usage are collected. H&E and immunohistochemistry slides were reviewed to analyze CD20, CD3 and PAX5 staining patterns. Results (if a Case Study enter NA) Of 14 cases, 10 cases showed cytoplasmic and granular staining with CD20, with extracellular spilling instead of the typical membranous pattern. This change was more frequent with intravenous dexamethasone (7/9) compared to oral prednisone (3/5), high dose (80%) compared to moderate and low dose (67%), short-term corticosteroids usage (86%) compared to intermediate-term and long-term (57%) usage and shorter dosing interval (100% in Q6H). The impact of prebiopsy corticosteroids was seen more on lymph node (5/7) compared to bone marrow (3/5). This cytoplasmic granularity was also observed in CD3 in the background non-neoplastic T lymphocytes in 25% of the cases. Though nuclear stains such as PAX5, Ki67, MUM1 and BCL6 also showed granularity in a significant number of cases, it was limited to the nucleus. Conclusion Pre-biopsy corticosteroids leads to alteration in CD20 staining pattern of the lymphoma cells leading to cytoplasmic granularity with extracellular spillage, which causes diagnostic challenge. This effect varies according to the type, route, dose, and duration of corticosteroids usage.