The induction of long-term potentiation (LTP) in the hippocampal CA1 region requires both presynaptic activity and large postsynaptic depolarization. A standard protocol for inducing LTP using whole-cell recording is to pair low-frequency synaptic stimulation (100–200 pulses, 1–2 Hz) with a depolarizing voltage-clamp pulse (1–3 min duration). In this standard protocol, a Cs+-based internal solution is used to improve the fidelity of the depolarization produced by voltage-clamp. In an attempt to induce LTP more rapidly, we tried to induce LTP by pairing high-frequency stimulation (200 pulses, 20–100 Hz) with a short depolarization (∼15 s). Surprisingly, we found that this protocol failed to induce LTP, even though large LTP (∼300% of baseline) could be induced by a subsequent standard protocol in the same cell. Pairing brief high-frequency stimulation at the beginning of a long depolarization (3 min) also did not induce LTP. However, the same high-frequency stimulation at the end of the long depolarization did induce LTP. When similar experiments were done with a K+-based internal solution, pairing high-frequency stimulation with a short depolarization did induce LTP. This indicates that the requirement for long depolarization is related to the use of Cs+. We speculate that, when recording is made with Cs+, a tetanus given at the beginning of depolarization initiates a process that inhibits N-methyl-d-aspartate (NMDA)–dependent LTP. This inhibitory process itself decays away during prolonged depolarization.