We describe a case of persistent polyclonal B-cell lymphocytosis (PPBL) studied by morphological, immunological, cytogenetic and molecular analysis. PPBL is a rare lymphoproliferative disorder with an unclear natural history. Although a few cases of malignancies are observed during PPBL, this disorder is usually considered to be an indolent syndrome. A longer follow-up in a larger number of patients is needed in order to clarify the natural history of PPBL and its potential to transform into a malignancy. As PPBL is a rare disease, establishing an international PPBL registry could be the most effective way to understand the natural history of this disease and to discover its etiologic factors.