Objective To apply the evidence-based treatment method to direct the clinical therapy of refractory chronic lymphocytic leukemia (CLL). Methods Such evidence-based medicine databases as The Cochrane Library (Issue 10, 2010), OVID database, PubMed (January 1992 to October 2010) and http://www.nccn.org/ were searched to find the clinical evidence with high quality and the optimum treatment was designed based on the patient’s preferences. Results Two RCTs and five CCTs were included. The available clinical evidence displayed that rituximab could improve the therapeutic effect of combined chemotherapy on the refractory CLL, the COP/CHOP regimens were effective for the fludarabine-resistant CLL, and hematopoietic stem cell transplantation could be an effective salvage therapy for the relapsed/refractory CLL, but not the first-line recommendation drug. This patient was treated by CHOP regimen combined with rituximab, the condition of disease was improved two months after stopping chemotherapy, and the follow-up was conducted. Conclusion Current evidence reveals that rituximab combined with CHOP regimen produces good tolerance with a better clinical outcome than that of CHOP regimen. Clinical practice results display that the combination of rituximab and CHOP regimen can bring good prognosis to the patient, but still needs high-quality evidence to prove．