A unique population of patients--children who developed recurrent acute lymphocytic leukemia (ALL) following cessation of initial prolonged therapy--was studied. During a 2-year period, 17 such children were admitted to a planned combination chemotherapy program. Complete bone-marrow remissions were achieved in 16 patients, and the median duration of second hematologic remissions was 216 days. These responses were significantly better than those obtained in seven patients who relapsed during the administration of continuation chemotherapy. Although the rate and duration of induced remissions were notably high, 9 of the 17 patients who relapsed off therapy have again developed recurrent leukemia. This result, together with the moderate toxicity encountered during treatment, indicates that more therapy is needed. The equal proportion of bone marrow and meningeal relapses was interpreted to mean that a secon course of preventive central nervous system therapy early in remission may be especially useful.