Sixteen patients with advanced non-small cell lung cancer were treated with a combination of low-dose interleukin-2 and tumor necrosis factor-alpha. Patients received a continuous 24-hour intravenous infusion of interleukin-2 at 1 X 10(6) Cetus U/m2 and a simultaneous daily intramuscular dose of tumor necrosis factor-alpha (25 to 100 micrograms/m2) for 5 consecutive days. These doses did not have antitumor activity when administered alone in previous trials. Treatment was given at 3-week intervals. Common side effects included fever, local skin reaction at the injection site of tumor necrosis factor-alpha, pancytopenia, and general malaise, all of which were reversible within 48 hours of cessation of therapy. The maximum tolerated doses with this combination were 1 X 10(6) U/m2/day of interleukin-2 and 50 micrograms/m2/day of tumor necrosis factor-alpha, with thrombocytopenia (less than 50K) being the dose-limiting toxicity. Twelve patients received two cycles or more and were evaluable for response. Measurable tumor regression occurred in four patients. An additional seven patients had radiographic stabilization of disease (median = 12 weeks) before progression. All patients had augmented lymphokine-activated killer and natural killer activity during therapy. Enhanced lysis of autologous tumor in vitro was demonstrated in four of four patients during therapy. We conclude that combination immunotherapy with low-dose interleukin-2 and tumor necrosis factor-alpha can mediate tumor regression and can be given with acceptable toxicity.