Changes in osmotic and hydrostatic pressure were found to modulate NMDA responses of cultured embryonic mouse neurons recorded in various patch-clamp configurations. In nucleated patches, NMDA currents were potentiated by reductions in external osmolarity and were reduced in hyper-osmotic solutions. These changes, which were greater for low concentrations of NMDA, were not observed for responses to kainate, glycine, or GABA. They could be mimicked by directly changing the pipette pressure in nucleated, outside-out, inside-out, and cell-attached patches. Osmosensitivity of NMDA responses was also observed in the whole-cell mode, but only after prolonged dialysis. Mechanosensitivity of NMDA receptors could have an important role in neuronal regions experiencing changes in membrane tension, such as spines or growth cones.