It is generally believed that relapse of acute leukemia heralds progression of the disease into a more aggressive stage. The biological behavior of leukemic cells collected from four patients with adult acute lymphoblastic leukemia (ALL) prior to treatment and at relapse was studied after engraftment into 28 unconditioned mice with severe combined immunodeficiency (SCID). Leukemic cells engrafted in all but one mouse, with major differences observed in the growth and aggressiveness of the leukemias. Recipient mice of cells derived from all patients at relapse died more rapidly in overt leukemia than those which were injected with cells obtained prior to induction treatment (P=0.0002). SCID mice that received cells from one patient at the time of diagnosis also died in terminal leukemia. Other SCID mice however, that received cells from the remaining three patients prior to treatment developed occult leukemia that was detectable in the blood or bone marrow with the use of polymerase chain reaction (PCR) or flow cytometry only. Leukemic cells recovered from mice with terminal leukemia exhibited a larger proliferating fraction than cells originally injected (P=0.004). Our results demonstrate, that during the evolution from initial presentation to relapse, ALL cells may acquire biological properties which render them more aggressive in SCID mice.