Mature T-cell lymphoid neoplasms are clonal proliferation of post-thymic T-cells, which are generally refractory to traditional chemotherapy regimens. The prognosis for most patients with these disorders, particularly those with relapsed disease, is poor. New treatment strategies are urgently needed. Alemtuzumab and pentostatin have been used as single agents in various T-cell neoplasms with response rates of up to 75% and 50%, respectively. Immunosuppression and opportunistic infections are the principal overlapping toxicities. We have treated 9 patients with T-lymphoid malignancies (5 T-PLL, 1 ATL, 1 γδ-T-cell hepatosplenic lymphoma, 2 T-LGL) on a phase II study of alemtuzumab 30 mg IV three times weekly for up to 3 months with concomitant pentostatin 4 mg/m2 weekly x 4 followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics including valcyclovir, trimethoprim/sulfamethoxazole, and fluconazole were administered during therapy and for 2 months after completion. Median age of patients was 57 years (range 25–80 years), median WBC was 78.5 x 109/L (range 0.7 – 279.5 x109/L), median serum β2M was 4.1 mg/L (2.7 – 10.8 mg/L). Six patients had splenomegaly (1 – 6 cm), and 3 lymphadenoapthy. Six had received prior therapy (median 5, range 1 to 6 regimens). To date, 6 of 8 evaluable patients have responded (5 CR, 1PR). One patient who had failed both single agent pentostatin and single agent alemtuzumab achieved CR with the combination. Monoclonal T-cell receptor gamma chain gene rearrangements were detected by PCR in all patients and became negative in 3 of 5 evaluable responding patients. Median response duration is 5+ months (range 2 – 6+ months). Two patients proceeded to an allogeneic stem cell transplant, 2 (1 with ATL and 1 with T-LGL) have died from disease progression after a response, 2 are alive and disease-free, and 2 were refractory to therapy. Opportunistic infections have included reactivation of CMV and HSV in one patient, recurrence of pre-existing Serratia pneumonia in 1 patient and Aspergillus pneumonia in 1 patient. We conclude that the combination of alemtuzumab and pentostatin is effective in T-cell neoplasms; infections can be prevented with prophylactic antibiotic therapy and close monitoring of patients.