Human recombinant interleukin-2 (rIL-2) induced interferon-gamma (IFN-gamma) release in vivo was studied in 16 renal cell carcinoma patients treated with low-dose s.c. rIL-2. The s.c. administration of rIL-2 resulted in a significant increase in circulating IFN-gamma in all patients within 6 to 8 hours as measured by enzyme-linked immunosorbent assay (ELISA). Total IFN-gamma release, as expressed by the area under the concentration curve (AUC), and IFN-gamma serum peaks following repetitive s.c. rIL-2 injection showed a direct dose distribution dependancy, whereby significantly higher levels of secondary IFN-gamma were achieved in patients treated with 10 million IU rIL-2/m2 q 12 hours when compared with patients treated with 20 million IU rIL-2/m2 q 24 hours. IFN-gamma release was suppressed significantly in one patient who had been pretreated with corticosteroids, while prior immunotherapy with rIL-2 had no measurable effect on secondary IFN-gamma release in this study. Cumulative secondary IFN-gamma secretion, as expressed by the AUC, and IFN-gamma serum peak concentrations in response to s.c. rIL-2 did not correlate with response to therapy or survival of rIL-2 treated renal cell carcinoma patients.