The administration of low doses of recombinant interleukin-2 (rIL-2) in vivo to patients with malignant neoplasms has been demonstrated to selectively increase the number of circulating natural killer (NK) cells in these patients. Recent evidence from SCID mouse models suggests that IgG subclass levels can be influenced by the presence and activity of NK cells. Therefore, we sought to examine the effect of rIL-2 infusions on human serum IgG subclass concentrations. We determined serum IgG subclass concentrations in 27 cancer patients receiving low-dose rIL-2 by daily continuous intravenous infusion. Eleven of these patients had active, metastatic, nonhematologic tumors; 16 patients had received IL-2 when they were in a minimal residual disease state after autologous or allogeneic bone marrow transplantation. Samples obtained before beginning IL-2 therapy and 8 to 10 weeks into therapy were tested. Treatment with IL-2 resulted in an increase in the percentage of CD56+ NK cells from 18% to 54% (P = .0001). A significant decrease in geometric mean IgG2 concentration from 2,017 micrograms/mL to 1,655 micrograms/mL was noted over this time interval (P = .03). Furthermore, the geometric mean IgG2 concentration after treatment was significantly lower than that of healthy controls (P = .026). In contrast, no significant changes in serum IgG1, IgG3, or IgG4 were noted during r-IL2 infusions. Our data suggest that rIL-2 treatment selectively decreases serum IgG2 concentrations. We speculate that increased NK cells mediate downregulation of human serum IgG2.