Increasing evidence supports a role for histamine as a neurotransmitter and neuromodulator in emotion and cognition. The H 3 receptor was first characterized as an autoreceptor that modulates histamine release and synthesis via negative feedback. Mice deficient in apoE (Apoe–/–) have been used to define the role of apoE in brain function. In the present study, we investigated the possible role of histamine H 3-receptor-mediated signaling in anxiety and cognition in mice Apoe–/–and wild-type mice. H 3 antagonists increased measures of anxiety in wild-type, but not Apoe–/–, mice. In contrast, H 3 antagonists similarly impaired object recognition in wild-type and Apoe–/–mice. In Apoe–/–mice, reduced negative feedback via H 3 receptors could contribute to increased signaling of H 1 receptors. Apoe–/–mice showed higher sensitivity to the anxiety-reducing effects of the H 1 receptor antagonist mepyramine than wild-type mice. These effects were dissociated from effects of mepyramine on the HPA axis. Compared to saline controls, mepyramine reduced plasma ACTH and corticosterone levels in wild-type, but not Apoe–/–, mice. These data support a role for apoE in H 3 receptor signaling. H 3 antagonists were proposed as a treatment for cognitive disorders such as Alzheimer's disease, which is associated with increased anxiety and cognitive impairments. As H 3 antagonists increase measures of anxiety and impair object recognition in wild-type mice, the use of H 3 antagonists in cognitive disorders may be counterproductive and should be carefully evaluated.