Based upon in vitro and clinical data suggesting antitumor activity of interleukin-2 (IL-2) plus tumor necrosis factor (TNF) in non-small cell lung cancer (NSCLC), we conducted two parallel pilot studies of the combination in patients with advanced disease. Eight patients at the University of Wisconsin received 6 x 10(6) international U/m2/day of IL-2 by continuous infusion on days 1-4, 8-11, and 15-18 with 50 micrograms/m2/day of TNF administered intramuscularly on the same days. Seven patients at the University of Pittsburgh received IL-2 as a continuous infusion for 5 days at a dose of 6 x 10(6) U/m2/day, every 14 days. TNF was administered intramuscularly on days 1 through 5, starting at a dose of 50 micrograms/m2. Patients with no evidence of grade 3 or 4 toxicity on the first cycle had their dose of TNF escalated from 50 to 100 and then to 150 micrograms/m2. No responses were observed. The therapy was not well tolerated, with 11 of 15 patients developing grade 3 or 4 toxicity at some point during their therapy. The most common grade 3 or 4 toxicities were pulmonary (6 episodes) or cardiac (4 episodes) events. Constitutional symptoms were common, but not dose-limiting. Despite the lack of observed responses, the median survival was 11 months, with one patient with metastatic disease alive over 30 months later. We conclude that IL-2 plus TNF was not effective in inducing responses in patients with advanced NSCLC, but the prolonged survival suggests a role for IL-2 in NSCLC, which needs to be further defined by means other than classic response criteria.