Systemic immunotherapy with recombinant interleukin-2 (rIL-2) via intravenous (i.v.) and subcutaneous (s.c.) administration produces objective responses in a proportion of advanced cancer patients. While most of the previous investigations chose the i.v. route for cytokine application, there is an increasing number of trials employing s.c. rIL-2 therapy. The comparison of reported response rates for i.v. versus s.c. therapy reveals no significant differences between these modalities. In an effort to describe systemic toxicities of s.c. cytokine therapy with regard to renal, metabolic, and hemodynamic abnormalities and to compare these effects to toxicities reported upon i.v. therapy, we retrospectively evaluated 148 treatment cycles of s.c. immunotherapy given to 107 outpatients. Our study cohorts consisted of 15 patients who received s.c. rIL-2 at doses of (4.8-14.4) x 10(6) IU m-2 day-1 5 days/week for a total of 8 weeks, 20 patients who received rIFN alpha 2b at (3.0-6.0) x 10(6) m-2 day-1 thrice weekly for a total of 6 weeks, and 72 patients who were given s.c. rILFN alpha 2b at 6.0 x 10(6) U/m2, three times per week, plus s.c. rIL-2 at (14.4-18.0) x 10(6) IU/m2 on days 1 and 2, followed by 4.8 x 10(6) IU m-2 day-1 5 days/week for 6 consecutive weeks. These treatment regimens were well tolerated in the outpatient setting; no toxic death occurred, and none of the patients developed life-threatening toxicity due to a capillary leak syndrome. Upon s.c. combination therapy, dyspnea at rest occurred in 6% of patients and grade III and IV hypotension occurred in 7% and 4%, respectively; plasma protein was significantly decreased (mean nadir +/- standard deviation, 67 +/- 5 g/l). In addition, s.c. therapy led to a significant increase in serum creatinine (mean peak +/- standard deviation, 115.1 +/- 21.4 mumol/l) and urea nitrogen (mean peak +/- standard deviation, 6.5 +/- 2.5 mmol/l); electrolyte disturbances and direct nephrotoxicity never caused major clinical symptoms. This was in marked contrast to a multitude of dose-limiting and life-threatening adverse reactions reported upon i.v. rIL-2 therapy. We conclude that palliative low to intermediate-dose s.c. rIL-2/rIFN alpha combination therapy, in contrast to i.v. treatment, can be administered in the ambulatory setting with good practicability and excellent safety. This outpatient regimen is as effective against metastatic renal cell cancer as the most aggressive i.v. rIL-2 protocol reported.