The induction of activity-dependent persistent increases in synaptic efficacy, such as long-term potentiation (LTP), is inhibited by behavioural stress. The question arises whether stress also affects the ability to induce persistent decreases in synaptic efficacy, such as long-term depression (LTD). We now report that the induction of stable homosynaptic LTD in the CA1 area of the hippocampus of awake adult rats is facilitated, rather than inhibited, by exposure to mild naturalistic stress. The same stress blocked the induction of LTP. The effects of such stress were short lasting: acclimatization to, or removal from, the conditions that facilitated LTD induction led to a rapid loss of the ability to elicit this form of plasticity. The time window in which LTD could be reliably elicited was prolonged by inducing anaesthesia immediately after the stress. These data reveal that even brief exposure to mild stress can produce a striking shift in the susceptibility to synaptic plasticity in the awake animal.