Tick salivary gland extract (SGE) was previously shown to inhibit murine T cell proliferation. In mice, SGE has an inhibitory effect on Th1 and a stimulatory effect on Th2 cytokine elaboration. In the present study, tick-mediated immunomodulation of human T cell proliferation and cytokine elaboration was analyzed using human peripheral blood mononuclear cells (PBMCs) stimulated with concanavalin A (Con A) or lipopolysaccharide (LPS). Using flow cytometry, tick saliva–induced changes were investigated in human mononuclear cell subpopulations. SGE from Ixodes ricinus dose-dependently inhibited human T cell proliferation. This finding supports the flow cytometry data, showing that the percentage of Con A–activated HLA-DR CD3 T lymphocytes and CD4 CD8 double-positive T cells decreased after SGE treatment. SGE significantly inhibited the in vitro production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) secreted by Th1 lymphocytes. In contrast, the elaboration of IL-4, IL-6, and IL-10 secreted by Th2 lymphocytes was significantly stimulated by I. ricinus SGE. Similarly, the production of both IL-1α and IL-1β was significantly stimulated after SGE treatment. These data indicate that the tick-induced immunomodulatory events in humans are similar to those previously described in a murine model.