While several studies have focused on preliminary data and outcomes associated with prehospital buprenorphine administration interventions, to date there has been little discussion of the challenges experienced during the initial implementation of a prehospital buprenorphine protocol. In this case series we examine 3 separate patient encounters with different crews, patients, and receiving emergency medicine (EM) physicians, which highlight initial challenges experienced with implementing the first prehospital buprenorphine program in a rural Appalachian County within South Carolina. In 2 cases we highlight conflicts that may require collegial intervention and education of local receiving EM physicians regarding the new prehospital protocol. In 1 case we describe a patient who was eligible but not enrolled due to a misunderstanding among an Emergency Medical Services (EMS) clinician of how to correctly apply protocol criteria. We discuss the management of each implementation issue and outcomes after follow-up with members of the study team. As these novel programs emerge, understanding the potential challenges and personal biases that may be encountered when implementing a prehospital buprenorphine administration protocol is essential to inform organizations planning to implement similar programs.