Although transfusion-dependent thalassemia causes physical and psychosocial impacts, little is known about adolescents’ experience in living with the disease. The knowledge of how adolescents live with their illness is expected to benefit patient focused nursing interventions to promote adolescents’ well-being. The purpose of this study was to understand and explain Thai adolescents’ experience of living with transfusion-dependent thalassemia. Grounded theory methodology was employed to generate a substantive theory to capture that experience. Data were gathered from thirteen Thai adolescents through in-depth interviews and analyzed concurrently through constant comparative analysis to generate a substantive theory. The adolescents were recruited by purposive and theoretical sampling. Theoretical saturation was a criterion to finish data collection. Living with the differences emerged as a core category of the substantive theory, and consists of four related categories: illness understanding; a sense of differences; emotional experiences; and, managing the differences. The findings provide better understanding of the experiences of Thai adolescents attempting to meet social expectations of normalcy in living with transfusion-dependent thalassemia. This understanding adds to prior knowledge of the disease and other chronic illnesses, and contributes to the development of nursing interventions to support adolescents to achieve well-being as they navigate life.