Abstract: This study demonstrates desalination using cross-flow Vacuum Membrane Distillation (VMD) under negative membrane pressure differences. The membrane pressure difference is defined as the partial pressure difference of water vapour between the upstream membrane surface and the downstream membrane surface. The negative membrane pressure differences are resulted from the low feed temperatures (40-60°C) and the high downstream pressures (14.5-40 kPa). The experimental results showed that positive fluxes (2-3.6 kg m-2 h) take place although the system is operated under the negative membrane pressure differences. The humidity on upstream side higher than the humidity on downstream side allows the water vapour transfers from the feed to the permeate sides. Relatively high feed temperatures and relatively low downstream pressures resulted in high enthalpy differences and hence high fluxes. The hydrostatic pressure on the feed circulation loop contributed a minor effect on the total flux when membrane pore wetting takes place. The rejection of salt under these conditions was at least 96%.