We conducted a phase II trial to evaluate the efficacy and toxicity of subcutaneous injections of recombinant interleukin (IL)-2 in 22 heavily pretreated patients with advanced cutaneous T-cell lymphoma. We observed modest response rates (18%) with a reasonable toxicity profile. The role of IL-2 in vivo for expansion of cytotoxic CD8⁺ T cells, CD4⁺ T cells, regulatory CD25⁺ T cells, or a combination of these has not been elucidated. There was no evidence of expansion of CD8⁺ T cells in peripheral blood of patients during treatment. Immunophenotypic analysis revealed an increase of CD25⁺ cells in CD3⁺ and CD4⁺ populations after treatment in a subset of patients possibly reflecting activation of reactive helper T cells, proliferation of neoplastic T cells, or proliferation of T-regulatory cells. In summary, at this dose and schedule recombinant IL-2 is largely ineffective as therapy in patients with advanced cutaneous T-cell lymphoma. Whether IL-2 has the potential to suppress antitumor activity by stimulation of regulatory T cells needs to be clarified.