Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder associated with memory loss, cognitive deterioration and weakness of intellectual capacity. Inheritance of the ε4 allele of the apolipoprotein E gene (ApoE4) is a major risk factor for the development of AD. Although the association between ApoE4 and AD is well documented, the effects of ApoE4 on hippocampal synaptic plasticity which related to long-term memory is unknown. In the present study, we recorded in vivo late-phase long-term potentiation (L-LTP) of field excitatory postsynaptic potentials (fEPSPs) in hippocampal CA1 region of rats, and investigated the possible electrophysiological mechanism of ApoE4 in the induction and maintenance of L-LTP. 60 male SD rats (250-350 g) were used. Under anesthesia with urethane (1.5 g/kg i.p.), the L-LTP was induced by three groups of high frequency stimulation (HFS); ApoE4 solution (0.2 μg, n=24; 2 μg, n=12) was injected into the hippocampus 30 min before HFS (pre-HFS injection) or 1 min after HFS (post-HFS injection). Control rats (n=24) received only saline. The paired pulse facilitation (PPF) in the CA1 region was also recorded. All values were presented as means±S.E.M. and ANOVA or t-tests was used for statistical analysis. The results showed that: (1) three groups of HFS successfully induced hippocampal L-LTP in control group, with average fEPSP amplitudes of 211.0±7.2%, 170.4±4.5% and 161.2±3.3% immediately, 60 min and 180 min post-HFSs, respectively; (2) in pre-HFS injection group, 0.2μg apoE4 did not change the base line synaptic transmission but significantly (p<0.01) inhibited the L-LTP induction, the fEPSPs being 178.3±5.8%, 149.7±5.0% and 142.2±5.0% at the same time points as control group; (3) in post-HFS injection groups, the same concentration (0.2μg) of apoE4 produced a slight, but not significant decrease in the average fEPSP amplitude ( p>0.05); further, injection of high dose (2μg) ApoE4 after HFS did not enhance the suppression of L-LTP, the fEPSPs still being 152.2±6.6% and 150.7±4.2% at the same time points ( p>0.05); (4) ApoE4 injection did not affect the PPF, the values before HFS being 164.8±3.4% and 163.2±3.0% in control and ApoE4 (0.2μg) groups, respectively (p>0.05); the values after HFS being 132.1±2.4%, 132.9±2.0% and 127.7±3.7% in control, 0.2μg ApoE4 and 2μg ApoE4 groups, respectively (p>0.05). These results indicate that ApoE4 injection before HFS, not after HFS, impaired hippocampal L-LTP, suggesting that neurotoxicity of ApoE4 is mainly involved in the suppression of L-LTP induction, but not the maintenance. In addition, the unaffected PPF suggests that the inhibition of L-LTP induction by ApoE4 may be not mediated by presynaptic neurotransmitter release, but postsynaptic signaling.