ABSTRACT Background: Despite the distinctive anaemic feature of Sickle Cell Disease (SCD), very little research has focussed on fatigue. Although evidence has highlighted fatigue as being a significant problem for adolescents with SCD, the nature of the fatigue experienced, and how the young people self-manage it is under-researched. Understanding how adolescents with SCD experience fatigue would provide a more holistic understanding about how young people with SCD experience life with the condition and ensure they receive optimum care, particularly in sub-Saharan Africa where the condition is of significant epidemiological and clinical importance, but care is significantly inadequate. Aim: To construct a theory, grounded in the fatigue experiences of adolescents with SCD in Ghana, to explain SCD-related fatigue in adolescence. Methods: A constructivist grounded theory approach was adopted. Data were collected from 24 eligible adolescents aged 12-17 years with sickle cell anaemia, who were registered with two sickle cell specialist clinics in Ghana. Eligible participants were recruited through initial purposive sampling, and subsequently through theoretical sampling until theoretical saturation was reached. Data were collected using in-depth audio-recorded conventional standalone or auto-driven photo-elicitation interview approaches. Written assent and proxy consent were obtained from the participating adolescents and their parents. Fieldnotes and a reflexive methodological journal were kept throughout the conduct of the research. Interviews were transcribed verbatim and translated where necessary into English and analysed using âCharmazianâ principles: initial, focused and theoretical coding, constant comparison, theoretical sampling and sensitivity, and memo-writing. Results: The grounded theory, Body as a Machine constructed from the data consists of a core category, âbody as a machineâ and its overlapping subcategories: âlosing the energyâ and âmanaging the energyâ. The theory embodies the discursively constructed meaning and representation of fatigue as experienced by the adolescents, the sociocultural issues underpinning their fatigue experiences, the consequences of fatigue, and the adolescentsâ management strategies. The adolescents perceived their bodies as machines with limited energy capacity and highly susceptible to fatigue due to SCD. Fatigue symbolised a major daily threat to the adolescentsâ sense of ânormalcyâ and identity. SCD-related fatigue is a stigmatised attribute, which subjected the young people to stigma and impacted on their emotional well-being. Fatigue was also closely linked to vaso-occlusive crises, the adolescentsâ future outlook and life goals. SCD-related fatigue was found to be at the front and centre of the adolescentsâ problems with SCD and underpinned their daily self-management actions. Conclusions: The theory suggests that fatigue is central to the young peopleâs day-to-day illness experience, impacting significantly on their self, social and emotional development and their ability to have fulfilling lives. Fatigue is an antecedent to the young peopleâs pain experiences, with extreme fatigue leading to severe painful crises. This highlights the importance for services and health professionals to focus symptom management interventions on fatigue rather than pain and psychological symptoms alone.