Acute tumor lysis syndrome resulting from rapid neoplastic cell lysis after chemotherapy is an unusual event, generally seen in histological aggressive lymphatic tumors. The authors saw four patients who developed acute tumor lysis syndrome when treated for advanced-stage, refractory chronic lymphocytic leukemia (CLL) with an initial cycle of cytosine arabinoside (Ara-C) 2 g/m2 every 12 hours x 4, cisplatin 35 mg/m2 every 24 hours x 2, and etoposide 100 mg/m2 every 24 hours x 2 (ACE). With aggressive hydration, urine alkalinization, forced diuresis, and high-dose allopurinol, acute tumor lysis syndrome was not seen in three subsequent cases of CLL treated with ACE. Of a total of eight patients treated, seven patients had marked reductions in lymphocyte counts after the first course of ACE. Of the eight patients, three are alive: one in a complete remission greater than 2 years, one in partial remission after three cycles of ACE, and one in Richter's transformation to large cell lymphoma. The remaining patients died after one cycle of ACE chemotherapy, one as a direct complication of acute tumor lysis and pancytopenia, and four others from complications of severe pancytopenia and general debilitation. Therefore, ACE appears to cause a rapid dissolution of tumor cells in CLL, and with appropriate aggressive management of the tumor lysis and infectious complications may have a favorable impact on survival in advanced CLL.