AIMS AND OBJECTIVES: Following a cross-sectional survey, a sub-sample of participants was interviewed to explore the interaction between symptoms and burden of treatment. BACKGROUND: Burden of treatment considers both the work associated with illness and treatment, including self-care work, as well as the individuals' capabilities and resources to engage in that work. The recent survey revealed the existence of a complex interaction. DESIGN: Qualitative abductive analysis of semi-structured interviews. METHODS: Adults with heart failure who participated in the survey were purposely sampled and invited to participate in semi-structured interviews. Location and mode of interview varied by participant choice. Excerpts from the verbatim transcripts were assessed for interactions between symptoms and burden of treatment, and when identified these were characterised and explained. We followed COREQ checklist for reporting. The patient research ambassador group was involved from research design to dissemination. RESULTS: Participants (n = 32) consistently discussed how symptoms altered their capability to engage in self-care work. As symptom intensity increased the difficultly of their self-care work increased. A number of intervening factors appeared to influence the relationship between symptoms and burden of treatment. Intervening factors included illness pathology, illness identity, the value of the tasks attempted and available support structures. These factors may change how symptoms and burden of treatment are perceived; a model was constructed to explain and summarise these interactions. CONCLUSIONS: The interaction between symptoms and burden of treatment is complex. Intervening factors-illness identity and pathology, task value and performance, and available support structures-appear to exert a strong influence on the interaction between symptoms and burden of treatment. RELEVANCE TO CLINICAL PRACTICE: These intervening factors present clinicians and researchers with opportunities to develop interventions that might reduce burden of treatment and improve symptoms and quality of life. CLINICAL TRIAL REGISTRATION: SYMPACT was registered with ISRCTN registry: ISRCTN11011943.