The halotolerant alga Dunaliella salina is a recognized model photosynthetic organism for studying plant adaptation to high salinity. The adaptation mechanisms involve major changes in the proteome composition associated with energy metabolism, carbon and iron acquisition. In order to clarify the molecular basis for the remarkable resistance to high salt, we performed a comprehensive proteomic analysis of the plasma membrane. Plasma membrane proteins were recognized by tagging intact cells with a membrane-impermeable biotin derivative. Proteins were resolved by two-dimensional Blue Native/SDS-PAGE and identified by nanoLC-MS/MS. Out of 55 identified proteins, about 60% were integral membrane or membrane-associated. We identified novel surface coat proteins, lipid metabolizing enzymes, a new family of membrane proteins of unknown function, ion transporters, small GTP-binding proteins and heat shock proteins. The abundance of 20 protein spots increased and of 2 protein spots decreased under high salt. The major salt-regulated proteins were implicated in protein and membrane structure stabilization, and within signal transduction pathways. The migration profiles of native protein complexes on BN gels revealed oligomerization or comigration of major surface-exposed proteins, which may indicate mechanisms of stabilization at high salinity.