Sézary Syndrome (SS) is an aggressive T-cell malignancy often presenting in advanced age and associated with poor prognosis. There is no standard therapy and because of co-morbidities, elderly patients are particularly challenging to treat. Alemtuzumab is an anti-CD52 monoclonal antibody that has activity in SS but is profoundly immunosuppressive, leading to great hesitation about its use in older patients. We treated five octogenarian patients with SS with subcutaneous (SQ) alemtuzumab, at relapse or as initial therapy, for 5-9 weeks. With the exception of transient grade 1-2 hematological toxicity and asymptomatic cytomegalovirus (CMV) (two patients) and Epstein-Barr virus (EBV) (one patient) reactivation, no other toxicities were observed. The clinical and hematological complete response (CR) rate was 100%. Three patients achieved durable responses (8+ to 17+ months). Alemtuzumab was safely administered and showed significant activity in very elderly SS patients.