Small cell lung cancer (SCLC) kills at least one person every 2 hr in the United Kingdom. Some patients do relatively well but most have rapidly progressive disease. There is no effective treatment and overall 2-year survival is less than 5%. Patients with SCLC have poorly understood local and systemic immune defects and can be immunocompromised. As CD4+ T lymphocytes coordinate and regulate immunity, a better understanding of interactions between SCLC tumour cells and CD4+ T cells may lead to effective molecular immunotherapy. We show that some, but not all, SCLC tumour cell lines secrete molecules that induce IL-10 secretion by and de novo differentiation of functional CD4+CD25+FOXP3+CD127loHelios− regulatory T (Treg) cells in healthy blood lymphocytes. FOXP3+ T cells were found in SCLC tumour biopsies, and patients with higher ratios of FOXP3+ cells in tumour infiltrates have a worse survival rate. The inhibitory effect of SCLC tumour cells was not affected by blocking IL-10 receptor or TGF-β signalling but was partially reversed by blocking IL-15, which is reported to be involved in human Treg cells induction. IL-15 was secreted by SCLC cells that inhibited CD4+ T-cell proliferation and was present in SCLC biopsy tumour cells. These novel findings demonstrate that SCLC tumour cells can induce CD4+ T-cell-mediated immunosuppression. This gives a potential mechanism by which SCLC tumour cells may downregulate local and systemic immune responses and contribute to poor patient survival. Our data suggest that IL-15 and Treg cells are potential new therapeutic targets to improve immune response and patient survival in SCLC.