We report the use of inhaled natural interleukin-2 in patients with metastatic disease. Six patients with metastatic renal cell carcinoma received 100,000 units natural interleukin-2, 5 times per day by inhalation in addition to a 4-day cycle of intravenous natural interleukin-2 every 2 weeks and subcutaneous interferon 5 days per week. Response was clearly correlated with metastatic site. Distinct tumor burden and the poor condition of the patient did not impair success. Pulmonary metastases responded in 5 of 5 patients. Metastases in the mediastinum, liver, abdomen and pelvis were stabilized in 4 patients. No response was noted in 3 solitary bone metastases, which were successfully removed surgically after several months of therapy, and a pleural metastasis progressed despite a clear response of the pulmonary disease in the same patient. New metastases did not develop in any of the patients during treatment (median followup 183 days of treatment, range 97 to 296 days). The over-all importance of the low toxicity of this novel route of administration (World Health Organization classification not exceeding grade 1) making long-term outpatient treatment possible must be emphasized because limitations of systemic interleukin-2 application are mainly caused by pulmonary side effects, for example pulmonary capillary leakage syndrome and edema. However, this new type of topical natural interleukin-2 application and combination with low dose intravenous interleukin-2 achieved considerable antitumor responses.