OBJECTIVES: Fludarabine (F) has been proven to be highly effective in the treatment of chronic lymphocytic leukemia (CLL). Both oral and IV F are used internationally. Recently, the oral formulation of fludarabine was approved in the US for treating CLL, which may offer advantages for providers, payers and patients. This study is a systematic review of clinical trial and retrospective data for oral and IV fludarabine, focusing on differences in efficacy, complications, resource utilization, cost and patient preference.  METHODS: PubMed and manual bibliographic searches were conducted to identify relevant publications for oral and IV F. Studies were included if they were: 1) published after January 1, 2000, 2) derived from human subjects, 3) written or translated in English 4) focused on CLL, and 5) evaluated efficacy, resource utilization, complications, costs or patient preference.  RESULTS: There were 17 articles that met inclusion criteria. Results indicated that the pharmacokinetic profile of oral and IV F were similar, with 25 mg/m2 of IV being equivalent to 40 mg/m2 of oral. Oral F has similar efficacy and safety to IV F, and eliminates infusion related adverse events and administration costs. Studies indicated that providing oral F was more convenient for patients and nurses due to the absence of IV administration. No cost or pharmacoeconomic data were found.  CONCLUSIONS: Oral and IV F were found to have similar clinical efficacy and safety. The oral formulation may potentially lead to substantial economic benefits when factoring in possible reductions in infusion related administration and adverse events. Future studies need to compare real-world clinical outcomes and economic impact of oral vs. IV F, taking into account decision-making in clinical practice of both health care providers and patients.