Membrane protein interactions are challenging to identify because of the unique biophysical characteristics of both transmembrane proteins and membrane environments. The Receptor Display in Membranes Interaction Screen (RDIMIS) platform overcomes these challenges by screening transmembrane and membrane-proximal proteins in a membrane environment using recombinant extracellular vesicles (rEVs). The screen has been used to successfully identify interactions for difficult-to-study receptors in an unbiased manner. In this report, we detail how we generate rEVs, characterize the rEVs to ensure screen-readiness, and perform the full interaction screening, with emphasis on the criteria necessary to obtain clear, interpretable results. We also include support protocols for generating a screening library and validating screening results, as well as an alternate protocol for RDIMIS enabling the profiling of naturally occurring extracellular vesicles.