The pro-inflammatory cytokine tumor-necrosis factor- α (TNF- α) is elevated in several neuropathological states that are associated with learning and memory deficits. Previous work has reported that TNF- α inhibits the induction of LTP in areas CA1 [Neurosci Lett 146 (1992) 176] and dentate gyrus [Neurosci Lett 203 (1996) 17]. The mechanism(s) underlying this process of inhibition have not to date been addressed. Here, we show that perfusion of TNF- α prior to long-term potentiation (LTP) inducing stimuli inhibited LTP, and that in late-LTP (3 h post-tetanus) a depression in synaptic field recordings was observed (68 ± 5%, n=6 versus control 175±7%, n=6, P<0.001). We investigated the involvement of the mitogen-activated protein kinase (MAPK) p38 in the inhibition of LTP by TNF- α as p38 MAPK has previously been shown to be involved in interleukin-1 β inhibition of LTP in the dentate gyrus [Neuroscience 93 (1999b) 57]. Perfusion of TNF- α led to an increase in the levels of phosphorylated p38 MAPK detectable in the granule cells of the dentate gyrus. The p38 MAPK inhibitor SB 203580 (1 μM) was found by itself to have no significant effect on either early or late phase LTP in the dentate gyrus. SB 203580 was found to significantly reverse the inhibition of early LTP by TNF- α (SB/TNF- α 174 ± 5%, n=6 versus TNF- α 120 ± 7%, n=6, P<0.001, 1 h post-tetanus) to values comparable to control LTP (control 175 ± 7%, n=6). Interestingly however, the depressive effects of TNF- α on late LTP (2–3 h) were clearly not attenuated by p38 MAPK inhibition (SB/TNF- α 132 ± 5%, n=6 versus control LTP 175 ± 7%, n=6, P<0.001, 3 h post-tetanus). This work suggests that TNF- α inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP.