Aims and background The purpose of the study was to investigate the IL-2/IL-2 receptor system in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods Sera from 40 subjects and 80 patients with stage III and IV NSCLC were assayed for soluble interleukin-2 receptor (sIL-2R) and interleukin-2 (IL-2) by the enzyme-linked immunosorbent assay. Circulating CD25+ cells were analyzed by flow cytoflorimetry. The data were related to clinical status by comparing the levels of slL-2R and IL-2 at diagnosis and during the treatment. Results The mean slL-2R concentrations of the NSCLC patients were significantly higher than the control population (P=0.0001); the patients with metastatic disease had significantly higher levels than those with locally advanced disease (P=0.02). No correlation was seen between circulating CD25+ cells and slL-2R levels. Disease progression was associated with an increase in slL-2R levels and a decline in IL-2; the sIL-2R/IL-2 ratio showed a gradual increase with tumor progression. Conclusions Our study demonstrates in a large series of patients that in advanced NSCLC there is an imbalance of the IL-2/IL-2 receptor system. Furthermore, circulating slL-2R levels and the sIL-2R/IL-2 ratio may be useful as markers of disease activity and treatment response, suggesting a potential prognostic value.