The combined administration of subcutaneous recombinant human interleukin-2 (rIL-2) and interferon-a (rIFN-~) was studied in a phase II trial on patients with advanced progressive renal cell cancer. Safety, tolerance and clinical response rate of this outpatient treatment protocol were assessed in 29 evaluable patients who received a total of 47 cycles, each consisting of s.c. rIL-2 at 14.4-18 million IU m-2day -1 on days 1 and 2, followed by 6 weeks of combined administration of s.c. rIL-2 at 3.6-4.8 million IU m -2 day -I on 5 days a week, and s.c. rIFN-a at 3-6 million units m -2 three times weekly over a period of 6 consecutive weeks. In patients exhibiting stable or regressive disease upon combined Ib2 and rIFN-a., the therapy was continued. The overall response rate was 31°70 (95 07o confidence limits = 15%-51%), with 6 out of 29 patients achieving partial remission (PR, 21 07o) and 3 patients complete remission (CR, 1007o). In addition, 12 patients presented with stable disease. The median duration of response was 8.5 months in PR and 19+ months in CR. Long-term treatment using this regimen was associated mainly with moderate (WHO grade I-II) toxicity including fevers, chills, malaise, nausea and/or vomiting, anorexia and transient local inflammation at the injection sites. No toxic deaths occurred. Altered thyroid function was observed in more than half the patients. The combination regimen resulted in a significant increase in peripheral blood eosinophils and natural killer cells (P< 0.005). Upon treatment, 14 patients developed non-neutralizing activity against rIL-2, and 2 of these developed specific neutralizing antibodies after consecutive cycles; no anti-rIFN-2b antibodies were detected. In summary, subcutaneous long-term outpatient treatment with low-dose rIL-2 and rIFN-a is feasible, with moderate toxicity, and results in an objective tumor response rate comparable to that obtained previously with high-dose rlL-2 i.v. regimens.