OBJECTIVE Kaposi's sarcoma-associated herpesvirus (KSHV) human herpesvirus type 8 (HHV-8) has been associated with Kaposi's sarcoma and a variety of benign lymphoid proliferations including angioimmunoblastic lymphadenitis with dysproteinemia and Castleman's disease. KSHV/HHV-8 has also been associated with inflammatory conditions including interstitial pneumonitis. Although herpesviruses are commonly associated with encephalitis in immunosuppressed individuals, KSHV/HHV-8 has not previously been associated with central nervous system disease other than lymphoma. The first cases of KSHV/HHV-8 associated encephalitis have been described. METHODS KSVH/HHV-8 sequences were evaluated in brain biopsies from three cases of otherwise unexplained encephalitis from three patients, two of whom were positive for HIV. Amplification of the polymerase chain reaction product was confirmed with Southern blot hybridization on three separate occasions, and with appropriate positive and negative controls. RESULTS All three cases of encephalitis were associated with KSHV/HHV-8 sequences. Characteristic lesions included endothelial cell swelling and perivascular cuffing by lymphocytes. CONCLUSIONS KSHV/HHV-8 was associated with encephalitis in immunosuppressed individuals, and should have been considered in the differential diagnosis of unexplained viral encephalitis. KSHV/HHV-8 may have tropism for the central nervous system.