Long-term potentiation (LTP) and long-term depression (LTD) are activity-dependent changes in synaptic strength that may serve as the cellular mechanisms of information storage in the vertebrate brain. The mossy fibre-CA3 synapse displays NMDA (M-methyl-D-aspartate) receptor-independent forms of LTP and LTD that were thought to be non-associative. Here we report that the mossy fibre-CA3 synapse displays each of the known types of LTD in vivo, including associative, heterosynaptic and homosynaptic LTD. These types of LTD are induced when only two of the three conditions necessary for mossy fibre LTP induction are provided. Because some of these conditions can be provided by convergent CA3 afferents, each type of LTD can be induced in an associative manner, which suggests that LTD is involved in associative information storage. Similar to the induction of NMDA receptor-dependent LTD and LTP at other cortical synapses, mossy fibre LTD occurs when synaptic conditions are insufficient to induce LTP, and both LTP and LTD induction are influenced by previous synaptic activity, consistent with the view that common principles govern activity-dependent plasticity at cortical synapses.