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A new O-ring flat sheet membrane module design was used to investigate the performance of Vacuum Membrane Distillation (VMD) for water desalination using two commercial polytetrafluoroethylene (PTFE) and polyvinylidene fluoride (PVDF) flat sheet hydrophobic membranes. The design of the membrane module proved its applicability for achieving a high heat transfer coefficient of the order of 103 (W/m2 K) and a high Reynolds number (Re). VMD experiments were conducted to measure the heat and mass transfer coefficients within the membrane module. The effects of the process parameters, such as the feed temperature, feed flow rate, vacuum degree, and feed concentration, on the permeate flux have been investigated. The feed temperature, feed flow rate, and vacuum degree play an important role in enhancing the performance of the VMD process; therefore, optimizing all of these parameters is the best way to achieve a high permeate flux. The PTFE membrane showed better performance than the PVDF membrane in VMD desalination. The obtained water flux is relatively high compared to that reported in the literature, reaching 43.8 and 52.6 (kg/m2 h) for PVDF and PTFE, respectively. The salt rejection of NaCl was higher than 99% for both membranes.