Glucose-regulated protein94 (Grp94) is the most represented endoplasmic reticulum-resident HSP with the unique property to modulate the immune response. This has opened the way to the use of Grp94 as effective therapeutic agent in both depressed and exaggerated activity of the immune system. We investigated the effect of native Grp94 on peripheral blood mononuclear cells (PBMCs) isolated from blood of two subjects with a different history of bronchial allergic asthma. Whereas in subject 1 an elevated basal level of Ig and altered morphological aspects of PBMCs suggested an intense antigen-driven stimulation of the immune system, subject 2 had an apparently normal basal humoral response. However, Grp94 reduced in a concentration-dependent manner the Ig secretion from PBMCs of both subjects, inhibition being maximal at 100 ng/ml Grp94 after 15 days. The effect was apparently related to inhibition of intra-cellular content of both IgG and IgE, and in subject 1 was still observed a year after the first examination. Dot-blot experiments revealed the presence of anti-Grp94 antibodies in Ig secreted from PBMCs and in plasma of both subjects, confirming the role of Grp94 as antigen responsible for activation of the immune system, even in the absence of clinical signs of asthma. Anti-Grp94 antibodies significantly decreased after PBMC treatment with Grp94 at 100 ng/ml. Results demonstrate that inhibition of the humoral response by Grp94 crucially depends on being Grp94, the antigen challenging the immune system in these allergic subjects, thus supporting the role of Grp94 as immuno-modulatory agent in pathologies with exaggerated immune response.