Altered neurogenesis in adult hippocampus is implicated in cognition impairment and depression. Inflammation is a potent inhibitor of neurogenesis. The cyclin-dependent kinase inhibitor p21Cip1 (p21) restrains cell cycle progression and arrests the cell in the G1 phase. We recently showed that p21 is expressed in neuronal progenitors and regulates proliferation of these cells in the subgranular zone of the dentate gyrus of hippocampus where adult neurogenesis occurs. The current study suggests that p21 is induced in vivo in the hippocampus of WT mice in response to acute systemic inflammation caused by LPS injections, restrains neuronal progenitor proliferation and protects these cells from inflammation-induced apoptosis. In intact p21−/− hippocampus, neuronal progenitors proliferate more actively as assessed by BrdU incorporation, and give rise to increased number of DCX positive neuroblasts. However, when mice were treated with LPS, the number of neuroblasts decreased due to induced subgranular zone apoptosis. In vitro, differentiating Tuj-1 positive neuroblasts isolated from p21−/− hippocampus exhibited increased proliferation rate, measured by Ki-67 staining, as compared to WT cells (p<0.05). In WT neuronal progenitors treated with IL-6, the number of p21-positive cells was increased (p<0.05), and this led to Tuj-1+ cell proliferation restraint, whereas the number of proliferating GFAP+ astrocytes was increased ∼ 2-fold. Thus, when p21 is intact, inflammation might divert neuronal progenitors towards astrogliogenesis by inducing p21. At the same time, when p21 is lacking, no effects of IL-6 on proliferation of Tuj-1+ cells or GFAP+ cells are detected in differentiating p21−/− neuronal progenitors. These results underscore the important role of p21 controlling hippocampal neuronal differentiation during inflammation. © 2013 Wiley Periodicals, Inc.