Previous research has shown that lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) administration produces learning/memory deficits in a variety of paradigms. In our laboratory, we have consistently observed LPS-induced behavioral alterations in a two-way active avoidance conditioning paradigm. Following LPS administration, one factor that affects cytokine production is corticotropin-releasing factor (CRF). CRF has well known anti-inflammatory effects, via stimulation of ACTH and corticosterone release. However, CRF acting directly on immune cells or within the CNS may potentiate proinflammatory effects. The current experiments explored the potential of antalarmin, a CRF-R1 non-peptide antagonist, to diminish or negate deficits observed with LPS administration. On the first day of testing, four-month-old male C57BL/6J mice received an intraperitoneal (i.p.) injection of antalarmin, followed 90min later by a second i.p. injection of LPS 4h prior to two-way active avoidance conditioning testing. As hypothesized, LPS administration altered performance. However, pretreatment with antalarmin attenuated the adverse effects of LPS administration. Moreover, evidence indicates that antalarmin attenuated hippocampal, but not peripheral, cytokine release. The behavioral results cannot be explained by alterations in the HPA axis, as antalarmin did not affect the LPS-induced rise in corticosterone. The current research contributes preliminary evidence that CRF may be an important factor in the development of LPS-induced behavioral effects, and that blocking the activity of CRF may be sufficient to alleviate some of the effects of endotoxin exposure, possibly due to diminished LPS-induced IL-1beta release in the dorsal hippocampus.