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CLL cells are thought to have diminished cell cycling capacity, a view challenged by their phenotypic resemblance to activated human B lymphocytes. The present study addresses the cell cycling status of CLL cells, focusing on those leukemic cells expressing CD38, a molecule involved in signaling and activation that also serves as a prognostic marker in this disease. CD38+ and CD38- members of individual CLL clones were analyzed for co-expression of molecules associated with cellular activation (CD27, CD62L and CD69), cell cycle entry (Ki-67), signaling (ZAP-70), and protection from apoptosis (telomerase and Bcl-2). Regardless of the size of the CD38+ fraction within a CLL clone, CD38+ subclones are markedly enriched for expression of Ki-67, ZAP-70, human telomerase reverse transcriptase, and telomerase activity. Although the percentage of cells (~2%) entering the cell cycle, as defined by Ki-67 expression, is small, the absolute number within a clone can be sizeable and is contained primarily within the CD38+ fraction. Despite these activation/proliferation differences, bot