How　polymer　synthesis　is　mobilized　or　activated　as　a　biological　response　of　Haloferax　mediterranei　against　hypertonic　conditions　remains　largely　unexplored.　This　study　investigated　the　protein　expression　of　H.　mediterranei　in　response　to　high　salinity　by　using　isobaric　tags　for　relative　and　absolute　quantitation　(iTRAQ)-based　proteomic　analysis.　The　microbes　were　harvested　at　end　of　fermentation　at　the　NaCl　salinity　of　75　and　250　g　L-1.　Among　the　identified　2123　proteins,　170　proteins　were　differentially　expressed.　Gene　ontology　annotation　revealed　that　the　highest　number　of　proteins　was　annotated　in　biological　process　category,　which　was　responsible　for　metabolic　process,　cellular　component　and　catalytic　activity.　Differentially　expressed　proteins　were　belonged　to　the　class　of　response　to　stimulus　as　well　as　catalytic　activity　and　binding.　Under　high　salinity　conditions,　three　pathways　were　established　as　key　responses　of　PHA　and　EPS　production　to　hypertonic　pressure.　Two　overexpressed　proteins,　beta-ketoacyl-ACP　reductase　and　3-hydroxyacyl-CoA　dehydrogenase,　enhanced　the　synthesis　of　PHAs.　The　serine-pyruvate　transaminase　and　serine-glyoxylate　transaminase　were　upregulated,　thereby　increasing　the　conversion　of　glucose　to　PHA.　Downregulated　levels　of　sulfate-adenylyl　transferase　and　adenylyl-sulfate　kinase　could　cause　diminished　EPS　synthesis.　This　study　could　contribute　to　better　understanding　of　the　proteomic　mechanisms　of　the　synthesized　polymers　in　defending　against　salt　stress.　Significance:　Haloferax　mediterranei,　a　family　member　of　halophilic　archaea,　is　well　known　for　its　fermentative　production　of　poly-beta-hydroxyalkanoates　(PHAs).　PHAs　are　natural　polymers　that　exhibit　great　potential　in　a　wide　range　of　applications　such　as　a　good　alternative　to　petroleum-based　plastics　and　the　biocompatible　material.　For　decades,　the　functional　role　of　PHAs　synthesized　by　H.　mediterranei　is　deemed　to　be　carbon　and　energy　reservations.　The　finding　proved　that　differential　production　of　PHA　and　EPS　in　H.　mediterranei　exposed　to　elevated　salinity　was　caused　by　differential　protein　expression.　This　is　the　first　report　on　how　PHA　and　EPS　synthesized　by　H.　mediterranei　is　mobilized　as　the　response　of　increased　salinity,　contributing　to　the　understanding　of　halophilic　archaea＇s　response　to　hypertonic　stress　and　the　precise　control　of　fermentation　production.　Despite　its　advantages　as　a　PHA　cell　factory,　H.　mediterranei　synthesized　EPS　simultaneously,　thereby　lowering　the　maximum　yield　of　PHA　production.　Overall,　salinity　can　be　used　as　a　vital　microbial　fermentation　parameter　to　obtain　the　highest　harvest　of　PHA,　as　well　as　the　lowest　EPS　synthesis　in　industrial　fermentation.