Suppression of T and B cell responses during invasive amebiasis may be serum mediated. The mechanism of serum-mediated suppression of spleen cell lymphoproliferation from gerbils with amebic liver abscess was examined. Compared with uninfected gerbil serum (10%), serum samples collected at days 10, 30, and 60, but not at day 20 after infection, augmented both concanavalin A (Con A; T cell mitogen)- and lipopolysaccharide (LPS; B cell mitogen)-induced proliferation of homologous spleen cells. Only day 20 serum (>5%) inhibited Con A- but not LPS-induced proliferation of spleen cells from uninfected gerbils. The suppressive mechanism was independent of nitric oxide and prostaglandin but involved reduced interleukin (IL)-2 production. Addition of exogenous IL-2 reversed the suppressive effect of day 20 serum on Con A-stimulated proliferation. These results identify a mechanism whereby serum may contribute to transient suppression of T cell responses during Entamoeba histolytica infections.