Fourty-three primary cerebral lymphomas (PCL) were histologically classified and examined for genome expression of Epstein Barr Virus (EBV) and human herpes virus 6 (HHV6) using dot blotting, polymerase chain reaction, and Southern blotting. Only 20 tumors (16 high grade and 4 low grade lymphomas) could be suitably placed into a category of the Updated Kiel Classification, whereas the non-classified 23 tumors were highly malignant B-lymphomas and referred to as small-cell (SC) or large-cell (LC) blastic PCL. Most of the LC PCL showed a tumor-like infiltration pattern with high cellular density and little remaining parenchyma, whereas the SC PCL more often showed an inflammation-like pattern characterized by loose arrangement of tumor cells and marked astrocytic, microglial and T-lymphocytic reaction. EBV genome was found in 3/3 AIDS cases, but in none of 40 immunocompetent cases, while HHV6 was detected in 2 tumors of immunocompetent patients. We conclude that (1) the Updated Kiel Classification is not applicable to a majority of PCL, and (2) EBV and HHV6 do not appear to play a major role in the pathogenesis of PCL in immunocompetent subjects.