The aim of the present study was to compare the outcome of patients affected by typical hairy cell leukemia (HCL) treated with interferon-alpha (IFN-alpha) and/or 2-chlorodeoxyadenosine (2CdA). Thirty-four consecutive patients were enrolled in the study. IFN was administered in 26 cases as first line therapy at a dose of 3 MU every other day for 12 months. 2CdA was given in 8 cases as first-line and in 14 cases as second-line therapy in patients resistant to (2 cases) or relapsed after (12 cases) IFN. The treatment schedule for 2CdA was 0.1 mg/kg/daily for 7 days for 1 cycle (17 patients) or 2 cycles (5 patients). Complete (CR) and partial remission (PR) were 19% and 58%, respectively, for IFN, 75% and 25% for 2CdA in first-line therapy, 86% and 14% for 2CdA in second-line therapy. Median progression-free survival for IFN patients was 19 months and no statistical advantage was detected for those who achieved a CR vs those in PR. In the group treated with 2CdA, only 1 patient (4%) relapsed after a median follow-up of 14 months. At a median follow-up of 59 months (range 4-134), overall survival of all 34 patients was 97%, with only 1 patient having died of an acute leukemia. Our results confirm the favorable outcome currently expected for HCL and emphasize the therapeutic activity of 2CdA in the treatment of this disease.