Staphylococcal enterotoxin A (SEA) is a superantigen that stimulates T cells and induces the production of multiple cytokines. Previous studies have shown that SEA augments gustatory neophobia and activates the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to determine if the cytokine response, behavioral effects, and HPA axis activation persisted after repeated SEA treatment. Male C57BL/6J mice were given 1-4 intraperitoneal injections of 5 microg SEA, after which food intake, corticosterone, or peripheral cytokines were measured. In a series of experiments, it was found that secondary exposure to SEA two or three days after priming increased corticosterone, but attenuated splenic TNFalpha, while augmenting IL-1beta, IL-2, and IFNgamma. The anorexic response was intact after secondary exposure, but absent after a third injection, which was still able to elevate corticosterone. It is unlikely that IL-1 mediated the persistent effects on corticosterone, since this was increased in groups lacking corticosterone elevations. Similarly, TNFalpha was only modestly elevated under repeated SEA conditions that elevated plasma corticosterone. This attenuation appeared to be inversely related to the levels of IL-10, the production of which incrementally rose with each successive injection. In conclusion, repeated exposure to SEA activates the HPA axis and alters behavior. However, there may be dissociation between the behavioral and endocrine effects of SEA with increased SEA exposure. Furthermore, it is possible that while TNFalpha was previously shown to be important in response to acute SEA-induced HPA axis activation, further exposure to SEA elicits other cytokines that may exert neuromodulatory effects through sensitization and/or synergistic mechanisms.