The proinflammatory cytokines tumor necrosis factor (TNFα), interleukin‐1 (IL‐1α), and interleukin‐6 (IL‐6) have been associated with various models of hippocampal damage. To examine their role in initiation of an acute hippocampal injury response, 21‐day‐old male CD‐1 mice received an acute intraperitoneal (i.p.) injection of trimethyltin hydroxide (TMT; 2.0 mg/kg) to produce necrosis of dentate granule neurons, astrocyte, and microglia reactivity. Tremors and intermittent seizures were evident at 24 hr. Intercellular adhesion molecule‐1 (ICAM‐1), glial fibrillary acidic protein (GFAP), anti‐apoptotic TNFα‐inducible early response gene (A‐20), macrophage inflammatory protein (MIP)‐1α, TNFα, IL‐1α, IL‐6, and caspase 3 mRNA levels were significantly elevated. Pretreatment with the antioxidant, ebselen, decreased ICAM‐1, A‐20, and TNFβ elevations. Pentoxifylline blocked elevations in A‐20 and decreased elevations in GFAP mRNA levels. Neither prevented histopathology or behavioral effects. Intracisternal injection of TNFα‐neutralizing antibody significantly inhibited both behavioral effects and histopathology. RNase protection assays showed that TMT‐induced elevations in mRNA levels for ICAM‐1, A‐20, GFAP, MIP‐1α, IL‐1α, TNFα, TNFβ, and caspase 3 were blocked by anti‐TNFα. These data demonstrate a significant role for TNFα in an acute neuro‐injury in the absence of contribution from infiltrating cells. The cerebellum shows limited if any damage after TMT; however, in combination with the i.c.v. injection, elevations were seen in GFAP and in EB‐22, a murine acute‐phase response gene homologous to the alpha (1)‐antichymotrypsin gene. Elevations were similar for artificial cerebral spinal fluid and anti‐IL‐1α, and significantly increased with anti‐TNFα, anti‐IL‐6, or the combination of antibodies. Responses seen in the cerebellum suggest synergistic interactions between the baseline state of the cell and manipulations in the cytokine environment. Data suggests a role for TNFα in the pathogenesis of hippocampal injury induced by TMT. Published 2003 Wiley‐Liss, Inc.