Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare haematological disorder. It is characterized by activated and morphologically atypical B lymphocytes and polyclonal IgM production and has been associated with female sex, cigarette smoking, and HLA-DR7 expression. We report a case of PPBL with intermitting symptoms compatible with a chronic fatigue syndrome, recurrent erythema nodosum and multiforme. Serological findings suggested a chronic active Epstein-Barr virus (EBV) infection. Messenger RNA of EBV immediate early gene transactivation BZLF1 was detected in peripheral blood lymphocytes by reverse transcriptase PCR indicating a persistent replication of the virus. Over 2 years of observation we detected varying numbers of atypical lymphocytes. These cells hybridized with a probe specific for the EBV internal repeat region (BamHI W) which indicates a productive infection. Of interest, no reaction was observed with a probe specific for the latency-associated small RNAs (EBERs). The immunological phenotype of the polyclonal B cells was similar to B-cell lines immortalized by EBV in vitro, expressing a number of activation molecules (CD23, CD25, CD54) and the bcl-2 protein. In summary, our findings suggest that persistent EBV replication might be crucial in the development of lymphoproliferative disorders such as PPBL.