Hippocampal neurogenesis is a lifelong process whereby new neurons are produced and integrate into the host circuitry within the hippocampus. It is regulated by a multitude of extrinsic and intrinsic regulators and is believed to contribute to certain hippocampal-dependent cognitive tasks. Hippocampal neurogenesis and associated cognition have been demonstrated to be impaired after increases in the levels of proinflammatory cytokine IL-1 beta in the hippocampus, such as that which occurs in various neurodegenerative and psychiatric disorders. IL-1 beta also suppresses the expression of TLX(orphan nuclear receptor tailless homolog), which is an orphan nuclear receptor that functions to promote neural progenitor cell (NPC) proliferation and suppress neuronal differentiation; therefore, manipulation of TLX represents a potential strategy with which to prevent the antiproliferative effects of IL-1 beta. In this study, we assessed the mechanism that underlies IL-1 beta-induced changes in TLX expression and determined the protective capacity of TLX to mitigate the effects of IL-1 beta on embryonic rat hippocampal neurosphere expansion. We demonstrate that IL-1 beta activated the NF-kappa B pathway in proliferating NPCs and that this activation was responsible for IL-1 beta-induced changes in TLX expression. In addition, we report that enhancing TLX expression prevented the IL-1 beta-induced suppression of neurosphere expansion. Thus, we highlight TLX as a potential protective regulator of the antiproliferative effects of IL-1 beta on hippocampal neurogenesis.