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To explore factors that influence presentation to an emergency department during ambulatory systemic anti-cancer therapy. This study was an exploratory qualitative study using semi-structured interviews. A purposive sample of adult patients with any cancer who had commenced systemic anti-cancer therapy in the ambulatory setting up to six months prior participated in semi-structured interviews between November 2016–December 2017. Interviews were transcribed verbatim, and data analysed thematically using a template analysis approach. Twenty patients and four caregivers took part. Five themes were generated from the interview data: 1) the unknown and unpredictable; 2) a change of lifestyle; 3) social determinants and access; 4) trust in care providers; and 5) the unavailability of care. As the number of systemic anti-cancer agents and patients eligible for them continues to grow, identifying, implementing and evaluating initiatives to mitigate emergency department presentations present an important area for health services research. Addressing timely access to trusted care and enhancing patient capacity for self-management present important areas for nurse-led system innovation. Findings from this study offer important insights into where and how nurses can mitigate emergency department presentations for individuals receiving systemic anti-cancer therapy by enabling accessible, coordinated and person-centred cancer care. • Uncertainty about what treatment-related side-effects to expect during systemic anti-cancer therapy, and difficulty determining the gravity of symptoms are important, nurse-sensitive drivers of emergency department utilisation. • Lack of access to healthcare from a trusted provider is a driver of emergency department presentation. Exploring individuals' capacity to access care is an important component of equitable nursing care. • Difficulty accessing hospital or community-based health professionals for advice regarding treatment side-effects during ambulatory cancer therapy contributes to emergency department presentations. These findings offer opportunity for nurse-led system-level innovation to deliver timely, equitable and accessible, person-centred care. [ABSTRACT FROM AUTHOR]