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BackgroundLow mood and distress are commonly reported by people who have persistent musculoskeletal (MSK) pain, which may be labelled as ‘depression’. It is important to understand how pain-related distress is conceptualised and managed in primary care consultations.AimTo explore understanding of pain-related distress and depression from the perspectives of people with persistent MSK pain and GPs.Design and settingQualitative study with people with persistent MSK pain and GPs from different parts of the UK.MethodSemi-structured interviews conducted remotely and data analysed thematically.ResultsMost participants reported challenges in distinguishing between distress and depression in the context of persistent MSK pain, but also described strategies to make this distinction. Some people described how acceptance of their situation was key and involved optimism about the future and creation of a new identity. Some GPs expressed ‘therapeutic nihilism’, with uncertainty about the cause of pain and how to manage people with both persistent MSK pain and distress in primary care consultations, while GPs who could identify and build on optimism with patients described how to help the patient to move forwards.ConclusionThis study offers a framework for the primary care consultation with patients presenting with pain-related distress. GPs should recognise the impact of persistent MSK pain on the patient and support the person in coming to terms with their pain, explore how the person feels about the future, encourage optimism, and support self-management strategies.