Four cases of central nervous system (CNS) lymphoma are reported which presented obstacles in diagnosis due to steroid treatment prior to biopsy. Reliable diagnoses were provided by molecular analysis. Malignant lymphoma of the CNS may be indistinguishable from other conditions, even in view of the gravity of the diagnosis. All patients had a previous history of glucocorticoid injection, for 2-18 days prior to stereotactic brain biopsy. The pathologic examination revealed in all cases axonal destruction and reactive gliosis with a variable infiltration of B- or T lymphocytes and macrophages. Characteristically, scattered degenerating small round cells with pyknotic or fragmented nuclei were also observed. However, the molecular assessment of paraffin-embedded tissues revealed the monoclonal IgH gene rearrangement, which allowed the confident diagnosis of B cell lymphoma. The histopathological findings of the present cases suggest that the tumor cells might be selectively destroyed by steroid treatment, which may render diagnosis impossible. Thus, molecular genetic investigation constitutes an important tool for establishing a diagnosis of CNS lymphoma obscured by steroid administration. This is especially true in cases where a paucity of tumor cells is observed or when monoclonality fails to be demonstrated by immunohistochemical tests.