Mevalonic acid can stimulate leukemic cells from some patients with B cell chronic lymphocytic leukemia (CLL) to enter the cell cycle in vitro and to synthesize DNA. Unlike normal human peripheral blood lymphocytes, which require the presence of granulocytes for a maximal DNA synthetic response to mevalonic acid, CLL cells do not require a helper cell. Only the physiologically active R(-) enantiomer of mevalonic acid is active in initiating DNA synthesis, and no stimulatory effect is noted after addition of the precursors of mevalonic acid or of its known products. The mitogenic responses to mevalonic acid measured in CLL cells from 35 patients varied widely (range of stimulation indices, 1.2–18.6), but the DNA synthetic response of CLL cells from 9 patients to mevalonic acid exceeded those seen with such common lymphocyte mitogens as concanavalin A, phytohemagglutinin, poke-weed mitogen, or a phorbol ester. The mevalonate-responsive CLL cell was enriched in the E(-), M(+) rosette subpopulation. When CLL cells were incubated in lipoprotein-depleted serum-containing medium, the presence of low density lipoprotein (LDL) cholesterol increased their sensitivity to mevalonic acid transformation, suggesting that a nonsterol product of mevalonic acid metabolism may be involved. Mevalonic acid, which is essential for the growth of cells programmed to divide or stimulated to divide by mitogens, can by itself initiate cell replication in relatively inert G0 phase normal and neoplastic lymphocyte populations.