The combination of purine analogs with alkylating agents is able to produce a synergistic antitumoral effect. However, the addition of immunosuppressive and DNA-targeting agents might increase purine analog-related complications. The risk for serious complications was evaluated in 38 patients treated with 2-chloro-2'-deoxyadenosine (CDA) and cyclophosphamide (CP). The diagnoses were chronic lymphocytic leukemia (CLL) in 15, Waldenström's macroglobulinemia in 4, mantle cell lymphoma in 6, follicular non-Hodgkin's lymphoma (NHL) in 10, and other low-grade NHL in 3 patients. All patients were pretreated (median: 2 lines, range: 1-5) and 23 (61%) were refractory. The patients received a median of two courses (range: 1-5) of 5.6 mg/m(2) CDA, followed by a median of 200 mg/m(2) CP, for 3 days. The response rate was 51% [complete remission (CR): 14%, partial remission (PR): 38%]. Grade 3/4 infections occurred in 16 (42%) patients. Dose-limiting cytopenias were seen in 22 (58%) patients. In 12 (32%) patients, autoimmune manifestations developed requiring treatment in most of them. Second cancers arose in five (13%) patients (myelodysplastic syndrome/acute myelocytic leukemia in three, lung cancer in two). Multivariate analysis showed that cytopenias, gender (F), prior radiotherapy, and age (>65 years) predicted for the complications seen after CDA-CP. To conclude, because of the high incidence of complications, caution is warranted in selecting patients with advanced lymphoid malignancies for the CDA-CP protocol.