Some patients with chronic lymphocytic leukemia (CLL) have a relatively stable clinical course without treatment, but many of these eventually develop progressive disease. We have followed 68 patients over 5 1/2 years by employing conventional surface markers and lymphocyte reactivity, including that of separate enriched T cells to their own leukemic B cells, to phytohemagglutinin (PHA), and to normal allogeneic B cells; we have observed an unusual response in each of the seven patients who developed progressive disease over this period of time. During the stable phase of the disease the T cells from 27 leukemic subjects did not respond to their own leukemic B cells in culture. In the seven patients who developed progressive disease, a significant reactivity of their enriched T cells to their own leukemic B cells occurred. There was no consistent change in T-cell reactivity to PHA or to allogeneic B cells, suggesting a change in the leukemic B-cell populations that was not detected morphologically. The change in reactivity of T cells to leukemic B cells occurred prior to evidence of clinical or laboratory deterioration in one of the seven cases; there was increasing lymphocytosis and lymphadenopathy in six and two instances, respectively; and anemia and thrombocytopenia in the three and one cases, respectively.