The goals of this study were to (1) introduce the MRI phenomenon of focal periphyseal edema (FOPE) to the orthopaedic community and (2) describe characteristic features and clinical outcomes of a small series of adolescents with FOPE lesions about the knee. The inclusion criterion was the presence of activity-related knee pain and periphyseal edema on T2-weighted MRI. Exclusion criteria were skeletal maturity, history of traumatic knee injury, and the presence of other knee abnormalities. Participants completed the Short Form 10 and Pediatric International Knee Documentation Committee (pedi-IKDC) outcome assessments. Four patients (average age, 13.7 years) with atraumatic activity-related knee pain and FOPE lesions were retrospectively identified. At follow-up (average, 15.8 months), all patients reported the ability to participate in physical activities at the desired level. The mean pedi-IKDC score was 71.2. With supportive treatment, patients with FOPE were able to return to sport, although they had lower-than-average outcome scores. Increased awareness and understanding of this clinical entity are necessary for provision of effective, cost-efficient care to patients with FOPE.