The purpose of this study was to determine the efficacy and toxicity of combined therapy consisting of rituximab (RIT), an anti-CD20 monoclonal antibody, and cladribine (2-chlorodeoxyadenosine, 2-CdA) (RC regimen) in patients with refractory or relapsed indolent lymphoproliferative disorders. Twenty six CD20 antigen positive patients, 15 with B-cell chronic lymphocytic leukemia (B-CLL) and 11 with low grade non-Hodgin's lymphoma (LG-NHL) were enrolled to the study. Fourteen patients (53.8%) had refractory disease, the other 12 (46.2%) were recurrent after prior chemotherapy. RC regimen consisted of RIT at a dose of 375 mg/m2 in 6 h infusion on day 1 and 2-CdA at a dose of 0.12 mg/kg, in 2 h infusion, given on days 2-6. The RC courses were repeated at 4 week intervals or longer if severe myelosuppression occurred. Seventy eight cycles of RC with median of 3 cycles per patient were administered (range 1-5 cycles). Four patients (15.4%) (95% CI 1.5-29.3%), 1 with B-CLL and 3 with LG-NHL, achieved a complete response (CR). Fourteen patients (53,8%) (95%CI 34.6-72.9%), including 10 with B-CLL and 4 with LG-NHL, had a partial response (PR). Overall response rate (OR) was 69.2% (95%CI 51.4-86.9%) in the whole group, from 63.6% (95% CI 35.2 92.0%) in LG-NHL to 73.3% (95%CI 50.1-95.7%) in B-CLL patients. Twelve of 18 patients with CR/PR are still in remission, with the median follow up 10 (7-28 months). The median failure-free survival (FFS) of responders was 6.5 months. Hypersensitivity to RIT was the major toxicity of RC regimen, and occurred in 9 patients (34.6%), mostly only during the first infusion of RIT. Severe neutropenia (grade III) was seen in 3 patients (11.5%). Anemia and thrombocytopenia associated with RC treatment were observed in 5 (19.2%) and 2 patients (7.7%), respectively. Four episodes (15.4%) of grade III-IV infections were observed. There was no treatment related mortality. During the follow-up six patients (23.1%) died from the disease progression. In conclusion, the combination of RIT and 2-CdA is an effective and well tolerated treatment, even for heavily pre-treated patients, and the results seem to be better than in patients previously treated in our institution with 2-CdA alone. This regimen can be considered as an alternative treatment of CD-20 positive indolent lymphoproliferative disorders.