Introduction. Previous research shows overweight children report poorer health-related quality of life (HRQoL), primarily in the areas of physical health and social functioning. These relations may be especially important to understand in rural populations characterized by poorer health behaviors and limited access to healthcare resources. Objective. The purpose of the current study was to investigate the relation between HRQoL (overall, physical, and social) and weight perception as well as actual weight status in middle school students residing in Southern Appalachia. Methods. 397 middle school students participating in Winning with Wellness, a school-based obesity prevention study, completed a written survey including the Pediatric Quality of Life Inventory. Results from a question on self-perceived weight were used to assign students to 1 of 4 weight-perception groups (underweight, healthy weight, overweight, or obese). Actual body mass index (BMI) percentile data collected by the schools was available for a subset of 152 students and used to classify students’ actual weight status according to Centers for Disease Control and Prevention guidelines. Results. Students who perceived them self to be overweight or obese reported significantly lower overall as well as lower physical and social HRQoL compared to students who perceived them self as a healthy weight. In the sub-sample with actual weight data, students whose actual weight status was obese reported significantly lower overall HRQoL than students whose weight status was in the healthy weight range. Conclusion. Our findings with students in Southern Appalachia are consistent with previous research documenting poorer HRQoL in overweight children and substantiate the need for more inclusive programs that target psychosocial well-being. The understanding of the role of weight perception in addition to actual weight may also inform future efforts at prevention and intervention.