Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75^NTR) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75^NTR, facilitates hippocampal long-term depression (LTD). Electron microscopy showed that p75^NTR localized in dendritic spines, in addition to afferent terminals, of CA1 neurons. Deletion of p75^NTR in mice selectively impaired the NMDA receptor–dependent LTD, without affecting other forms of synaptic plasticity. p75^NTR−/− mice also showed a decrease in the expression of NR2B, an NMDA receptor subunit uniquely involved in LTD. Activation of p75^NTR by proBDNF enhanced NR2B-dependent LTD and NR2B-mediated synaptic currents. These results show a crucial role for proBDNF-p75^NTR signaling in LTD and its potential mechanism, and together with the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBDNF and mature BDNF.