BACKGROUND: The COVID-19 pandemic and associated restrictions caused major global disruption. Individuals with long-term physical health conditions (LTCs) are at higher risk of severe illness and often subject to the strictest pandemic guidance, so may be disproportionally affected. The aim of this study was to qualitatively explore how living with a LTC during the COVID-19 pandemic affected people's mental health and wellbeing. METHODS: Participants were people living with LTCs who participated in telephone/video call interviews based on a semi-structured topic guide. Key themes and subthemes were determined using deductive and inductive thematic analysis. RESULTS: The sample included 32 participants with LTCs (most commonly cancer, respiratory conditions or cardiovascular diseases), mean age 57 (SD 13) years, 66% female and 72% white British. There were four overarching themes specific to living with a LTC. These were 1) high levels of fear and anxiety related to perceived consequences of catching COVID-19, 2) impact of shielding/isolation on mental health and wellbeing, 3) experience of healthcare during the pandemic and 4) anxiety created by uncertainty about the future. Fourteen subthemes were identified, including concerns about accessing essential supplies and the importance of social support. Individuals who lived alone and were advised to shield could be profoundly negatively affected. CONCLUSIONS: This study found that there were a number of aspects of living with a LTC during the pandemic that had a significant impact on mental health and well-being. There should be focus on how best to provide practical and social support to people with LTCs during a pandemic, particularly if they have to shield or isolate.