Large granular lymphocytic leukemia (LGLL) is characterized by the clonal proliferation of cytotoxic T lymphocytes or NK cells. Standard first-line immunosuppressive treatments have limitations, achieving complete remission (CR) rates of up to 50%. Immune system dysregulation is implicated in LGLL. Promising results for thalidomide, an immunomodulatory drug, combined with prednisone and methotrexate (TPM), were observed in our pilot study. This multicenter study evaluated the efficacy and safety of a thalidomide, prednisone, and methotrexate (TPM) regimen in 52 symptomatic, methotrexate- and thalidomide-naive LGLL patients from June 2020 to August 2022. Thalidomide (100 mg daily for up to 24 months), prednisone (0.5-1.0 mg/kg every other day, tapered after 3 months), and methotrexate (10 mg/m