The purpose is to determine the incidence of active and latent human herpesvirus-6 (HHV-6) infection in a large cohort of adult primary and recurrent CNS tumors. We screened a tissue microarray (TMA) containing more than 200 adult primary and recurrent CNS tumors with known clinical information for the presence of HHV-6 DNA by in situ hybridization (ISH) and protein by immunohistochemistry (IHC). One hundred six of 224 (47%) CNS tumors were positive for HHV-6 U57 Major Capsid Protein (MCP) gene by ISH compared to 0/25 non tumor control brain (P = 0.001). Fourteen of 30 (47%) tumors were HHV-6 MCP positive by nested PCR compared to 0/25 non-tumor brain controls (P = 0.001), revealing HHV-6 Variant A in 6 of 14 samples. HHV-6A/B early (p41) and late (gp116/64/54) antigens were detected by IHC in 66 of 277 (24%) (P = 0.003) and 84 of 282 (35%) (P = 0.002) tumors, respectively, suggesting active infection. HHV-6 p41 (P = 0.645) and gp116/64/54 (P = 0.198) antigen detection was independent of recurrent disease. Glial tumors were 3 times more positive by IHC compared to non glial tumors for both HHV-6 gp116/64/54 (P = 0.0002) and HHV-6 p41 (P = 0.004). Kaplan Meier survival analysis showed no effect of HHV-6 gp116/64/54 (P = 0.852) or HHV-6 p41 (P = 0.817) antigen detection on survival. HHV-6 early and late antigens are detected in adult primary and recurrent CNS tumors more frequently in glial tumors. We hypothesize that the glial-tropic features of HHV-6 may play an important modifying role in tumor biology that warrants further investigation.