Objective To assess the clinical effectiveness and safety of fludarabine and cyclophosphamide (FC) combined with rituximab chemotherapy regimen (FCR regimen) for patients with chronic lymphoblastic leukemia (CLL). Methods The databases such as PubMed, The Cochrane Library, SpringerLink, CNKI, and CBM were searched from 2000 to 2011. The randomized controlled trials (RCTs) on FC regimen versus FCR regimen for CLL were retrieved. The methodological quality of the included studies was assessed according to the Cochrane Reviewer’s Handbook, and meta-analyses were performed using RevMan 5.0 software. Results Three RCTs involving 1 623 patients with CLL were included. The results of meta-analyses showed that significant differences were found in the progression-free survival (PSF)(Plt;0.001), overall response (OR=1.94, 95%CI 1.49 to 2.53, Plt;0.000 01), complete remission (OR=2.54, 95%CI 2.00 to 3.22, Plt;0.000 01), and grade III or IV neutropenia (OR=1.60, 95%CI 1.33 to 1.92, Plt;0.000 01); but no significant differences were found in the partial response (OR=0.74, 95%CI 0.35 to 1.55, P=0.43), grade III or IV thrombocytopenia (OR=0.97, 95%CI 0.74 to 1.27, P=0.83) and autoimmune hemolytic anemia (OR=0.86, 95%CI 0.59 to 1.27, P=0.45) between FCR and FC regimen. Conclusion The FCR regimen can improve the progression-free survival, overall response and complete remission. Meanwhile, it sometimes increases the incidence of Grade III or IV events, such as neutropenia, thrombocytopenia, autoimmune hemolytic anemia and nausea and vomiting.