The effect of serotonin 5-HT2 receptor stimulation on long-term potentiation (LTP) in the primary visual cortex was investigated by using rat brain slices in vitro. Field potentials evoked by stimulation of layer IV were recorded in layer II/III. The 5-HT2 receptor agonist 1-(2,5-dimethyl-4-iodophenyl)-2-aminopropane (DOI) did not affect baseline synaptic potentials evoked by single-pulse test stimulation, but significantly inhibited the induction of LTP in a concentration-dependent manner (0.1–10 μm). The LTP-inhibiting effect of DOI (10 μm) was blocked by the 5-HT2,7 receptor antagonist ritanserin (10 μm), but not by the 5-HT1A receptor antagonist NAN-190 (10 μm) nor by the 5-HT3,4 receptor antagonist MDL72222 (10 μm). The inhibitory effect of DOI was also blocked by the phospholipase C inhibitor U73122, but not by its inactive analogue U73343. These results suggest that visual cortex LTP is inhibited by activation of the 5-HT2 receptor–phospholipase C system. In addition, the LTP-inhibiting effect of DOI was abolished by the presence of the GABAA receptor antagonist bicuculline (10 μm), suggesting that 5-HT2 receptor-mediated inhibition of visual cortex LTP is dependent on GABAergic inhibition.