In addition to functional disorders of paresis, paralysis, and cardiopulmonary complications, subsets of West Nile virus (WNV) patients may also experience neurocognitive deficits and memory disturbances. A previous hamster study has also demonstrated spatial memory impairment using the Morris water maze (MWM) paradigm. The discovery of an efficacious therapeutic antibodyMGAWN1 from pre-clinical rodent studies raises the possibility of preventing or treating WNV-induced memory deficits. In the current study, hamsters were treated intraperitoneally (i.p.) with 32 mg/kg of MGAWN1 at 4.5 days after subcutaneously (s.c.) challenging with WNV. As expected, MGAWN1 prevented mortality, weight loss, and improved food consumption of WNV-infected hamsters. The criteria for entry of surviving hamsters into the study were that they needed to have normal motor function (forelimb grip strength, beam walking) and normal spatial reference memory in the MWM probe task. Twenty-eight days after the acute phase of the disease had passed, MGAWN1- and saline-treated infected hamsters were again trained in the MWM. Spatial memory was evaluated 48 h after this training in which the hamsters searched for the location where a submerged escape platform had been positioned. Only 56% of infected hamsters treated with saline spent more time in the correct quadrant than the other three quadrants, as compared to 92% of MGAWN1-treated hamsters (P ⩽ 0.05). Overall these studies support the possibility that WNV can cause spatial memoryimpairment and that therapeutic intervention may be considered.