Summary Cortico-hippocampal interactions during sleep are believed to reorganize neural circuits in support of memory consolidation. However, spike timing relationships across cortico-hippocampal networks, which are key determinants of synaptic changes, are not well understood. Here we show that cells in prefrontal cortex fire consistently within 100 ms after hippocampal cells in naturally sleeping animals. This provides evidence at the single cell-pair level for highly consistent directional interactions between these areas within the window of plasticity. Moreover, these interactions are state-dependent: they are driven by hippocampal sharp-wave/ripple (SWR) bursts in slow-wave sleep (SWS) and are sharply reduced during REM sleep. Finally, prefrontal responses are non-linear: as the strength of hippocampal bursts rises, short-latency prefrontal responses are augmented by increased spindle band activity and a secondary peak ~100 ms later. These findings suggest that SWR events serve as an atomic unit of hippocampal-prefrontal communication during SWS, and that the coupling between prefrontal and hippocampal areas is highly attenuated during REM sleep.