Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare disorder of unknown aetiology affecting predominantly young to middle-aged women. It is characterized by a polyclonal expansion of B cells, including typical binucleated lymphocytes, and is associated with the presence of the translocation t(14;18), involving the bcl-2 oncogene. The stage of differentiation of the B cells expanded in PPBL is not known. We analysed the immunophenotype of the expanded B-cell subset in five new patients with PPBL and found a large uniform expansion of a recently defined human memory B-cell population, IgD(+)CD27(+) memory B cells. After in vitro stimulation with interleukin 2 (IL-2) and Staphylococcus aureus Cowan strain I, B cells from PPBL patients produced high levels of IgM immunoglobulins, which is a characteristic feature of IgD(+)CD27(+) memory B cells. Using a quantitative real-time polymerase chain reaction method, we found a high frequency of the translocation t(14;18) in the range of 1000-3000 per 106 B cells in PPBL patients. In contrast, a much smaller number of cells with a t(14;18) was found in B cells from healthy individuals. Our finding that PPBL is an accumulation of memory B cells further suggests that chronic antigeneic stimulation plays an important part in the pathogenesis of this disorder. This IgD(+)CD27(+) memory B-cell population might harbour a certain number of 'physiological' t(14;18) translocations that increases as this population expands in PPBL patients and constitutes the majority of peripheral blood lymphocytes.