Repetitive stimulation of synaptic connections in the cerebral cortex often induces short-term synaptic depression (STD), a property directly related to the probability of transmitter release and critical for the computational properties of the network. In order to explore how spontaneous activity in the network affects this property, we first studied STD in cortical slices that were either silent or that displayed spontaneous rhythmic slow oscillations resembling those recorded during slow wave sleep in vivo. STD was considerably reduced by the occurrence of spontaneous rhythmic activity in the cortical network. Once the rhythmic activity started, depression decreased over time in parallel with the duration and intensity of the ongoing activity until a plateau was reached. Thalamocortical and intracortical synaptic potentials studied in vivo also showed stronger depression in a silent than in an active cortical network, and the depression values in the active cortical network in vivo were indistinguishable from those found in active slices in vitro. We suggest that this phenomenon is due to the different steady states of the synapses in active and in silent networks.