Mycosis fungoides is an indolent primary cutaneous T-cell lymphoma (CTCL) that usually progresses from localized skin lesions to systemic disease. Sézary syndrome is a distinct variant characterized by generalized erythroderma and circulating cerebriform cells in the peripheral blood. The malignant cell in both diseases is a mature T cell, usually with a CD4-positive, CD8-negative phenotype. Among the treatment modalities used in these diseases are skin-directed therapy, single-agent and combination systemic chemotherapy, and, more recently, bioimmunotherapy. Pentostatin (Nipent), a potent inhibitor of adenosine deaminase, has activity in a wide range of lymphoid malignancies. At The Royal Marsden Hospital, we treated 29 cutaneous T-cell lymphoma patients with pentostatin, including 16 with Sézary syndrome, 5 with mycosis fungoides, and 8 with other cutaneous T-cell lymphomas. The median age of patients was 61 years (range, 26 to 87 years), with a male-female ratio of 2.5:1. The majority (N = 20) had received prior therapy. Pentostatin was administered at a dose of 4 mg/m2/wk for 4 weeks, and injections were continued every 1 to 2 weeks until maximum response. The overall response rate was 35%. However, only patients with Sézary syndrome achieved a good response, demonstrating an overall response rate of 62% (three complete responses plus seven partial responses). The median disease-free interval for responders was 9 months (range, 3 to 84 months). There was no significant treatment-related toxicity. We conclude that pentostatin is an effective single-agent therapy for patients with Sézary syndrome but not for those with other cutaneous T-cell lymphomas.