Compared with common airliners, High/Medium Altitude Long Endurance (HALE/MALE) RPAS are lighter and have larger wingspan. Therefore RPAS will be extremely sensitive to vortex interactions with larger airliners, not only during departures and arrivals, but also at medium and high altitudes during the en-route phase. The extent of this sensitivity shall be investigated in order to determine safe levels of separation and come up with feasible maneuvers to avoid the effect of wake vortex under the assumption that the RPAS may become unrecoverable by the autopilot. For this reason, the objective of this paper is to model the generation of en-route vortex and quantify its impact into the airworthiness of a potentially conflicting RPAS. To accomplish this objective, a wake vortex generation and encounter model will be created as a first step to define the airliner-RPAS separation requirements due to the airliner’s vortex. Then, vortex separation requirements will be compared to those usually employed for separation assurance. Conclusion will show that some current separation standards are not conservative enough when the RPAS faces an airliner wake vortex.