Background <p>Histiocytic proliferative disorders in the central nervous system are rare, and their potential association with viral infections remains largely unexplored. This case is relevant because it suggests a potential interaction between SARS-CoV-2 neuroinvasion and tumor development, providing insights into how viral infections might influence oncogenesis.</p> Case presentation <p>A 4.5-month-old male k18-hACE-2 mouse, part of an experimental study of SARS-CoV-2, displayed a small mass in leptomeningeal area composed by neoplastic round cells. This process is associated with typical acute inflammatory and neurodegenerative lesions according to viral neuroinvasion. Histopathology revealed a well-demarcated tumor composed of lymphoblasts and intermixed with abundant histiocytic-like cells. Immunohistochemistry showed high expression of Iba-1 in histiocytes but negative PAX5, CD3 and IRF-4 labeling. Due to the critical role of PAX-5 in maintaining B-cell function, its reduction or inactivation may favor this loss of identity and differentiation to macrophages, which supports the possibility of a lymphoma undergoing transdifferentiation into a histiocytic/dendritic cells neoplasm. Additionally, SARS-CoV-2 was detected within the tumor histiocytes and adjacent neurons, raising questions about potential interactions between viral infection and tumor development.</p> Conclusions <p>While the underlying mechanisms remain uncertain, this finding highlights the need for further investigation into the interplay between SARS-CoV-2 infection and oncogenesis. This case represents the first report of a primary brain histiocytic lymphoproliferative disorder associated with SARS-CoV-2 in k18-hACE2 mouse.</p>