BACKGROUND: A substantial subset of patients with major depressive disorder (MDD) experience treatment-resistant depression (TRD), typically defined as failure to respond to at least two sequential antidepressant trials at adequate dose and length. AIMS: To examine clinical and service-level associations of TRD, and the experiences of people with TRD and clinicians involved in their care within a large, diverse National Health Service trust in the UK. METHOD: This mixed-methods study integrated quantitative analysis of electronic health records with thematic analysis of semi-structured interviews. Chi-squared tests and one-way analysis of variance were used to assess associations between lines of antidepressant treatments and sociodemographic and clinical variables, and binary logistic regression was used to identify associations of TRD status. RESULTS: Nearly half (48%) of MDD patients met TRD criteria, with 36.9% having trialled ≥4 antidepressant treatments. People with TRD had higher rates of recurrent depression (odds ratio = 1.24, 95% CI: 1.05-1.45, CONCLUSIONS: TRD is characterised by increasing mental and physical morbidity and functional decline, with individuals experiencing barriers to effective care. Improved pathways, service structures and more effective biological and psychological interventions are needed.