We evaluated the effects of the addition of escalating doses of tumor necrosis factor (TNF) to two fixed doses and schedules of a combination of interleukin-2 (IL-2) and interferon-α (IFN-α) to determine the maximum tolerated dose of this three-cytokine combination and its feasibility as an outpatient regimen. Eighteen patients with metastatic cancer were enrolled. Each course consisted of 3 consecutive weeks of treatment with IFN-α 9 × 106 IU/m2/day intramuscularly (i.m.) or subcutaneously (s.c.) days 1, 3, and 5 each week for 3 weeks plus IL-2 continuous infusion 1 × 106 IU/m2/day (group A) or 3 × 106 IU/m2/day (group B) days 1-5 each week for 3 weeks. TNF was administered only during the first week of each course intravenously (i.v.) for 2 h on days 1-5. The dose of TNF was escalated (40, 80, 120 μg/m2) in cohorts of 3 patients. The most common side effects were fever, chills, and fatigue in all patients. Grade 3-4 toxicity included anemia (3 patients), thrombocytopenia (1 patient), arrhythmia (2 patients), pulmonary edema (3 patients), and weight loss (1 patient). Five patients withdrew from study due to toxicity. The combination of the three cytokines is feasible as an outpatient regimen in one of the following combinations: (a) TNF 80 μg/m2/day as 2-h infusion on days 1-5 + IL-2 1 × 106 IU/m2/day continuous infusion on days 1-5 for 3 weeks + IFN-α 9 × 106 IU/m2/day s.c. or i.m. on days 1, 3, and 5 for 3 weeks, or (b) TNF 40 μg/m2/day as a 2-h infusion on days 1-5 + IL-2 3 × 106 IU/m2/day continuous infusion on days 1-5 for 3 weeks + IFN-α 9 × 106 IU/m2/day s.c. or i.m. on days 1, 3, and 5 for 3 weeks.