Chronic lymphocytic leukemia (CLL) patients with aggressive molecular characteristics such as deletion of 17p13.1 do not respond to conventional treatments and have a shorter survival. Studies suggest that high-dose methylprednisolone (HDMP) has activity in such patients and combining HDMP with rituximab may enhance efficacy. We identified 37 patients with CLL treated with the HDMP-rituximab who had follow-up at Mayo Clinic. Nine of 27 (33%) had deletion of 17p13.1 and six of 27 (22%) had deletion of 11q22.3. After a median of one cycle of HDMP-rituximab, 29 (78%) patients had an objective response according to the National Cancer Institute CLL Working Group Criteria including five of nine patients with deletion of 17p13.1. Eight (22%) patients had a complete clinical response. Although well tolerated, 11 (29%) patients developed infectious complications before completing one month of therapy. Three-year survival was 41% (95% CI: 26 - 66%). HDMP-rituximab is an active regimen in patients with relapsed, refractory, and cytogenetically high-risk CLL. Further evaluation of this regimen in controlled trials appears warranted.