Ninety patients with advanced refractory chronic lymphocytic leukemia (CLL) were treated with 2-chlorodeoxyadenosine (2-CdA) administered either as a 0.1 mg/kg/day 7-day continuous intravenous infusion or as a 0.028 mg to 0.14 mg/kg/day 2-hour bolus for 5 consecutive days. One patient had stage A disease, seven patients had stage B disease, and 82 patients had stage C disease. Twenty-seven patients were female and 63 were male, with an age range of 40 to 84 years, median 63 years. All patients had received prior therapy and failed, with a range of one to four and a median of two prior therapies. Six patients had previously failed fludarabine therapy. Four patients (4%) experienced complete remissions, and 40 patients (40%) experienced partial remissions, yielding an over all response rate of 44%. The median duration of response was four months, with a range of two to 30 months. Of 50 patients who were non-responders, 27 (54%) had a greater than 50% sustained reduction in the absolute lymphocyte count despite insufficient improvement in hemoglobin concentration or platelet count to achieve a response status. Therapy was well tolerated with myelosuppression being the principal toxicity. Twenty-two patients (24%) experienced thrombocytopenia and 16 patients (18%) had documented infections. We confirm our early pilot results with 2-CdA demonstrating in a large group of patients that 2-CdA achieves a significant response rate with two different drug administration schemes in failed CLL patients. Responses are achieved with acceptable toxicity. 2-CdA merits further evaluation in previously untreated patients and in combination regimens for failed patients.