Introduction Aeromedical transport of patients with highly−infectious diseases, particularly over long distances with extended transport times, is a logistical, medical and organizational challenge. Following the 2014–2016 Ebola Crisis, sophisticated transport solutions have been developed, mostly utilizing large civilian and military airframes and the patient treated in a large isolation chamber. In the present COVID−19 pandemic, however, many services offer aeromedical transport of patients with highly−infectious diseases in much smaller portable medical isolation units (PMIU), with the medical team on the outside, delivering care through portholes. Methods We conducted a retrospective review of all transports of patients with proven or suspected COVID−19 disease, transported by Jetcall, Idstein, Germany, between April 1 and August 1, 2020, using a PMIU (EpiShuttle, EpiGuard AS, Oslo, Norway). Demographics and medical data were analyzed using the services’ standardized transport protocols. Transport−associated challenges and optimization strategies were identified by interviewing and debriefing all transport teams after each transport. Results Thirteen patients with COVID−19 have been transported in a PMIU over distances up to 7,400 kilometers (km), with flight times ranging from 02:15 hours to 11:10 hours. We identified the main limitations of PMIU transports as limited access to the patient and reduced manual dexterity when delivering care through the porthole gloves and disconnection of lines and tubes during loading and unloading procedures. Technical solutions such as bluetooth−enabled stethoscopes, cordless ultrasound scanners and communication devices, meticulous preparation of the PMIU and the patient following standardized protocols and scenario−based training of crew members can reduce some of the risks. Discussion Transporting a patient with COVID−19 or any other highly infectious disease in a PMIU is a feasible option even over long distances, but adding a significant layer of additional risk, thus requiring a careful and individualized risk−benefit analysis for each patient prior to transport.