BACKGROUND Human herpesviruses types 4 and 6 (EBV, HHV-6) are frequently found in Hodgkin 's disease (HD) and--to a certain extent--in Kikuchi-Fujimoto's disease (KFD). Both viruses are apparently related to proliferative and/or apoptotic processes as represented by HD or KFD respectively. OBJECTIVE To correlate frequency and location of antigen- and DNA expression of both viruses in HD and KFD tissue sections in relation to markers for cell proliferation and apoptosis. STUDY DESIGN Archival lymph node biopsies from 103 patients with HD and 14 KFD patients were investigated immunohistologically for viral antigen expression (EBV LMP- 1: HHV-6 pl 10/60), Ki67/PCNR, marker for proliferation (MIB1)/p53 and WAF1 for apoptosis. Viral DNA was shown by in situ hybridization. Apoptosis was determined by ISEL and TUNEL techniques. RESULTS HD is frequently infected by both EBV and HHV-6 while KFD tends to be infected only by HHV-6. EBV in HD is present in HD cells and in Reed-Sternberg cells (HD/RS cells), HHV-6 preferentially in lymphocytes and in histiocytes in both HD and in KFD. Proliferation marker Ki67 is found in lymphocytes and histiocytes of both diseases and in HD and RS cells in HD. Apoptosis is demonstrated in lymphocytes and histiocytes preferentially in KFD and to a lesser extent also in HD. CONCLUSION Although EBVand HHV-6 may not be openly oncogenic in HD and KFD, they may well influence the course of the disease. Dual infection in HD appears to support proliferative processes, i.e. a predominance of EBV effects. Single infection with HHV-6 in KFD instead appears to favor an apoptotic course. These effects are--according to the literature--possibly cytokine-mediated.