A total of 107 cancer patients were treated with 148 cycles of subcutaneous (SC) immunotherapy employing interleukin-2 (rIL-2) and/or interferon-alpha (rIFN-alpha). The systemic toxicities of SC cytokine therapy were retrospectively evaluated with regard to hepatic and metabolic adverse effects, and compared to adverse effects previously reported upon high- or intermediate-dose intravenous (IV) rIL-2 therapy. Our study cohorts consisted of 15 patients who received SC rIL-2 at doses of 4.8-14.4 million IU/m2/day on 5 days per week for a total of 8 weeks, 20 patients who received rIFN-alpha 2b at 3.0-6.0 million U/m2/day thrice weekly for a total of 6 weeks, and 72 patients who were given SC rIFN-alpha 2b at 6.0 million U/m2/day thrice weekly plus SC rIL-2 at 14.4-18.0 million IU/m2/day on days 1 and 2, followed by 4.8 million IU/m2/day, 5 days per week for 6 consecutive weeks. These treatment regimens were well tolerated in the outpatient setting; no toxic deaths occurred, and none of the patients developed life-threatening toxicity. Upon SC rIL-2/rIFN-alpha combination therapy, we observed mild decreases in plasma protein and albumin levels (mean nadir +/- standard deviation, 67 +/- 5 g/L and 38.8 +/- 3.9 g/L, respectively), minor albeit significant increases in serum total bilirubin levels (mean peak +/- standard deviation, 7.8 +/- 3.1 mumol/L), serum aspartate aminotransferase (25.9 +/- 9.9 U/L), alanine aminotransferase (42.0 +/- 45.9 U/L), alkaline phosphatase (301 +/- 255 U/L), lactate dehydrogenase (230 +/- 64 U/L), gamma-glutamyl transpeptidase (147 +/- 141 U/L) activities and triacylglyceride (2.6 +/- 0.9 mmol/L) concentrations. Cholinesterase activities (mean nadir +/- standard deviation, 42.6 +/- 13.7 kU/L), and serum cholesterol levels (4.4 +/- 0.9 mmol/L) decreased upon SC rIL-2/rIFN-alpha combination therapy. These mild clinical side effects and laboratory changes were in marked contrast to a multitude of dose-limiting and life-threatening adverse reactions described upon IV rIL-2 therapy. It is concluded that low-to intermediate-dose SC rIL-2/rIFN-alpha combination therapy as used in this study, can be given in the outpatient setting with good practicability and excellent safety.