This phase 2 study evaluated the safety and efficacy of alemtuzumab in 22 patients with advanced mycosis fungoides/Sézary syndrome (MF/SS). Most patients had stage III or IV disease, reduced performance status, and severe itching. The overall response (OR) rate was 55%, with 32% of patients in complete remission (CR) and 23% in partial remission (PR). Sézary cells were cleared from the blood in 6 of 7 (86%) patients, and CR in lymph nodes was observed in 6 of 11 (55%) patients. The effect was better on erythroderma (OR, 69%) than on plaque or skin tumors (OR, 40%) and in patients who had received 1 to 2 previous regimens (OR, 80%) than in those who had received 3 or more prior regimens (OR, 33%). Itching, self-assessed on a 0 to 10 visual analog scale, was reduced from a median of 8 before treatment to 2 at end of therapy. Median time to treatment failure was 12 months (range, 5-32+ months). Cytomegalovirus (CMV) reactivation (causing fever without pneumonitis and responding to ganciclovir) occurred in 4 (18%) patients. Six additional patients had suspect or manifest infection (fever of unknown origin, 3; generalized herpes simplex, 1; fatal aspergillosis, 1). One patient had fatal Mycobacterium pneumonia at 10+ months. All serious infectious adverse events (except CMV) occurred in patients who had received 3 or more prior regimens. Progression of squamous cell skin carcinoma was noted in 1 patient. Alemtuzumab shows promising clinical activity and an acceptable safety profile in patients with advanced MF/SS, particularly in patients with erythroderma and severe itching and those who were not heavily pretreated.