Objective: Present a pair of clinical cases demonstrating the utilization of regional interdependent (RI) evaluation and treatment in an apparent lateral ankle sprain. The utilization of both Positional Release Therapy (PRT) and Mulligan Concept (MC) on secondary school athletes with an apparent acute lateral ankle sprain are presented. Background: Lateral ankle sprains are a common injury in athletics. While the MC has been shown to be an effective manual therapy in ankle sprains, if the treatment is not pain-free it is considered not warranted. The concept of RI attempts to connect apparently unconnected dysfunctions within the body which collectively contribute to a patient’s complaint of pain or pathology. Treatment: The patients were successfully treated in one treatment session using a RI approach after failing to obtain a PILL effect while using MC during their initial evaluation. The patients experienced minimal clinically-important changes on a variety of patient related outcomes. Uniqueness: To the author’s knowledge, there are currently no published articles reporting the use of RI methods of evaluation and treatment in apparent lateral ankle sprain pathologies. Conclusion: The utilization of an RI approach as an evaluation and treatment technique in patients suspected of having acute lateral ankle sprains.