Our previous observation on immune modulation induced by a given factor VIII (F VIII) concentrate preparation was extended by showing that the immune-modulating capacity is a more general feature of F VIII products and is independent of product purity. Interaction of human monocytes with therapeutic concentrations of various F VIII concentrates (0.2 to 2 IU F VIII/mL, six different F VIII concentrates from four manufacturers) led to a significant reduction in the expression of IgG Fc receptors in the membrane of these cells (F VIII concentrate-induced downmodulation of the receptor). This Fc receptor downmodulation was achieved by a short (1-hour) incubation of human monocytes with F VIII concentrates 16 hours prior to the Fc receptor assay and did not correlate with the respective product's IgG content. Although the IgG concentrations of the different products varied greatly (from 1.0 to 177.3 mg/1,000 IU F VIII), all products behaved comparably with respect to Fc receptor downmodulation (F VIII-treated monocytes: 34% +/- 7% to 44% +/- 4% rosette-forming cells; controls in the absence of F VIII: 83% +/- 5%). Furthermore, we also were able to demonstrate that heat treatment of F VIII, now used by virtually every manufacturer to eliminate contaminating viruses, had no effect on the respective products' Fc receptor-modulating capacity. The immune-modulating component was characterized as being a high-molecular-range compound containing IgG, IgM, F VIII, and blood group substances (most likely a combination of immune complexes and immunoglobulin aggregates). This compound is present in comparable amounts in both high-purity and intermediate-purity products and apparently copurifies with F VIII during the manufacturing process.