AbstractRecent evidence suggests a role for tumor necrosis factor alpha (TNF) in the functioning of the central nervous system (CNS). The aim of this work was to examine the effect of a deficiency of TNF (TNF−/−) and its main receptors (TNF‐R1−/− and TNF‐R2−/−) on cognitive function. A standardized survey on cognition‐like behavior assessing learning and retention, spatial learning/memory, cognitive flexibility, and learning effectiveness was used in B6.WT and B6.TNF gene targeted mice strains (B6.wild‐type, B6.TNF−/−, B6.TNF‐R1−/−, B6.TNF‐R2−/− mice). All studied mice strains demonstrated successful exploration and learning processes during the training phases of the tests, which made the specific cognition‐like tests valid in these mice strains. In the specific cognition‐like tests, the B6.TNF−/− mice demonstrated significantly poorer learning and retention in the novel object test compared to B6.WT, B6.TNF‐R1−/− and B6.TNF‐R2−/− mice. In addition, spatial learning and learning effectiveness were significantly poorer in B6.TNF−/− mice compared to B6.WT mice. Moreover, the moderately impaired cognitive performance with similar degrees in B6.TNF‐R1−/− or B6.TNF‐R2−/− mice was generally better than in TNF−/− mice but also poorer than in B6.WT mice. While the absence of TNF was correlated with poor cognitive functioning, the deletion of both TNF‐receptors was involved in partially reduced cognitive functioning. Low‐levels of TNF under non‐inflammatory immune conditions appear essential for normal cognitive function. TNF displays an interesting candidate gene for cognitive function. Translational research is required to investigate associations between genetic variants of TNF and cognitive function in healthy subjects and neuropsychiatric samples. © 2008 Wiley‐Liss, Inc.