Considering rIFN-gamma as a potent biological response modifier (BRM), we started an open phase II trial with rIFN-gamma in patients with advanced renal cell carcinoma (RCC). For optimization of the dose and schedule of rIFN-gamma, two biochemical serum markers, neopterin and beta-2 microglobulin, were chosen to monitor the biological response. In order to test the magnitude and kinetics of rIFN-gamma-induced neopterin and beta-2 microglobulin release in the serum, rIFN-gamma was administered thrice at three different dose levels in a randomly assigned order (0.01; 0.1; 0.5 mg). Neopterin and beta-2 microglobulin were assessed by means of commercially available radioimmunoassays. The results revealed: 1) strong, reproducible and dose-dependent increments of both markers after the first injection 2) downregulation of the magnitude of neopterin responses with repeated injections at each of the three dose levels tested, and 3) a dose-dependent downregulation of the magnitude of beta-2 microglobulin responses and of serum baseline values at the highest dose level tested. From these data, we conclude that both the dose and schedule might be of importance for optimization of biological responses to exogenously applied rIFN-gamma.