Tumor necrosis factor alpha (TNFα) is a cytokine produced mainly by cells of the immune system. It is also expressed by brain neurons and glia. The physiological role of TNFα in the brain is not yet fully clear. Using TNFα-deficient mice, we have examined its role in hippocampal development and function. We report here that TNFα is involved in the regulation of morphological development in the hippocampus. TNFα-deficient mice exhibited an accelerated maturation of the dentate gyrus region and smaller dendritic trees in CA1 and CA3 regions in young mouse. In addition to its involvement in hippocampal morphogenesis, TNFα deficiency specifically improved performance of affected mice in behavioral tasks related to spatial memory. Moreover, lack of TNFα increased the expression of nerve growth factor (NGF), but not brain-derived neurotrophic factor (BDNF), following performance of the learning task. Our results suggest that TNFα actively influences hippocampal development and function. In adult mice, TNFα may interfere with memory consolidation, perhaps by regulating NGF levels.