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This study presents a comprehensive analytical framework to design efficient single-stage membrane distillation (MD) systems for the desalination of feed streams up to high salinity. MD performance is quantified in terms of energy efficiency (represented as a gained output ratio, or GOR) and vapor flux, both of which together affect the specific cost of pure water production. Irrespective of the feed salinity, permeate or conductive gap MD (P/CGMD) perform better than direct contact MD (DCMD) when the heat transfer resistance of the gap (in P/CGMD) is lower than that of the external heat exchanger in DCMD. Air gap MD’s (AGMD) better performance relative to the other configurations at high salinity and large system area can be explained in terms of its thicker ‘effective membrane’, which includes the air-gap region. CGMD and DCMD employing a thick membrane are also resilient to high salinity, similar to AGMD …