The increase of fludarabine-resistant chronic lymphocytic leukemia (CLL) presents a new treatment challenge. The aim of this review is to evaluate the efficacy and safety of rituximab for patients with fludarabine-refractory CLL. Medline, Embase, The Cochrane Library and selected conference proceedings were searched. Seventeen relevant publications reporting stratified data were identified. Treatments included: rituximab in combination with etanercept, alemtuzumab, bendamustine or methylprednisolone alone, with fludarabine and cyclophosphamide (FCR), with oxaliplatin as well as fludarabine and cytarabine, with cyclophosphamide as well as fludarabine and alemtuzumab (CFAR), and with cytarabine, cisplatinum and dexamethasone (DHAP). One study evaluated rituximab with granulocyte-macrophage colony-stimulating factor in combination with alternating cyclophosphamide, liposomal daunorubicin, vincristine, dexamethasone and methotrexate plus Ara-C. One study evaluated rituximab as monotherapy. Of the nine studies considering overall response, eight reported rates above 50% (four reported rates above 75%). Median overall survival was 37 months for FCR, 11 months for CFAR, 20 months for rituximab with methylprednisolone, 30 months for rituximab with alemtuzumab and 44 months for an FCR/CFAR mixed treatment. The identified studies indicate that regimens containing rituximab may be highly efficacious in the fludarabine-refractory CLL setting. Nevertheless, further research is needed to facilitate the choice of treatment for the clinician.