Cladribine (2-CdA) and fludarabine are the new purine analogs introduced in the treatment of chronic lymphocytic leukemia (CLL). Despite the high response rate, their influence on survival is still uncertain. The aim of this study was a retrospective analysis and comparison of the response rate and survival of CLL patients treated with high dose chlorambucil (HDChl) as first and 2-CdA as second line, with an historical group of patients never treated with purine analogs who received standard doses of chlorambucil (SDChl). We analyzed 347 patients with CLL treated between January 1985 and January 2000. Group A (190 patients) received HDChl (12 mg/m(2) ) with prednisone (P) 30 mg/m(2) daily for 7 days monthly as first line and in refractory or early relapsed patients 2-CdA (0.12 mg/kg/day) for 5 days with or without P (30mg/m(2) ) as second line. Group B (157 patients) received continuous SDChl (4-8 mg/m(2) /day) and P as first line and COP or CHOP as second line. The overall response rate (OR) for the first line was 48,4% in group A and 38,9% in group B (p=0.09). 148 patients in group A and 52 in group B received the second line treatment and the second OR was 19.6% and 13.5%, respectively (p=0.4). At the time of analysis, 124 patients died in group A and 139 in group B. Median survival was 65 months and 50 months, respectively. In group A, survival was longer in advanced Rai stage patients (p=0.001) but in early Rai stage was similar for both groups (p=0.4). We suggest that intensive treatment with HDChl as first line and 2-CdA as second line should be applied in more advanced rather than in less advanced stages of CLL until the final results of randomized clinical trials are available.