Questions: (1) With respect to outcomes such as survival, response rate, response duration, time to progression, and quality of life, is alemtuzumab a beneficial treatment option for patients with B-cell chronic lymphocytic leukemia (CLL)? (2) What toxicities are associated with the use of alemtuzumab? (3) Which patients are more likely—or less likely— to benefit from treatment with alemtuzumab? Perspectives: Evidence was selected and reviewed by one member of the Hematology Disease Site Group (DSG) of Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) and by methodologists. The practice guideline report was reviewed and approved by the Hematology DSG, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to obtain feedback from practitioners in Ontario. Outcomes: Outcomes of interest were overall survival, quality of life, response rates and duration, and adverse event rates. Methodology: A systematic review of the MEDLINE, EMBASE, HealthStar, CINAHL, and Cochrane Library databases was conducted to search for primary articles and practice guidelines. The evidence informed the development of clinical practice recommendations. The evidence review and recommendations were appraised by a sample of practitioners from Ontario, Canada, and were modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body within the PEBC. Results: The literature review found no published randomized controlled trials (RCTS) that evaluated alemtuzumab alone or in combination with other chemotherapeutic agents for the treatment of relapsed or refractory CLL. One RCT evaluated alemtuzumab administered to consolidate a complete or partial response to firstline fludarabine-containing chemotherapy. That study was stopped early because of excessive grades 3 and 4 infection-related toxicity in the alemtuzumab arm. Patients receiving alemtuzumab experienced significantly improved progression-free survival as compared with patients undergoing observation. Six single-arm studies evaluated disease response with administration of alemtuzumab as a single agent in the treatment of patients with relapsed or refractory CLL post-fludarabine. The pooled overall response rate was 38% (complete response: 6%; partial response: 32%). Adverse events associated with the use of alemtuzumab were commonly reported and included serious infusion-related, hematologic, and infection-related toxicities. Recommendation: This evidence-based recommendation applies to adult patients with B-cell CLL. Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic CLL that is refractory to both alkylator-based and fludarabine-based regimens. Qualifying Statements: The evidence supporting treatment with alemtuzumab comes principally from case series that evaluated disease response as the primary outcome measure. Patients should be informed that any possible beneficial effect of alemtuzumab on other outcome measures such as duration of response, quality of life, and overall survival are not supported in evidence and currently remain speculative. Treatment with alemtuzumab is associated with significant and potentially serious treatment-related toxicities. Patients must be carefully informed of the uncertain balance between potential risks of harm and the chance for benefit reported in studies. Given the current substantial uncertainty in this balance, patient preferences will likely play a large role in determining the appropriate treatment choice. Given the potential toxicities associated with alemtuzumab, and given the limited nature of the agent’s testing in clinical trials in broad populations of patients with CLL, the use of alemtuzumab in patients with important comorbidities may be associated with excessive risks.